使用5-羟色胺再摄取抑制剂150例病人的不良反应分析

目的 :了解选择性 5 羟色胺再摄取抑制剂(SSRIs)氟西汀、舍曲林、帕罗西汀的不良反应特点 ,增强对 5 羟色胺 (5 HT)综合征的认识。方法 :用自制不良反应调查表对 15 0例使用上述 3药的病人发生的药物不良反应进行调查。结果 :发现有 7例出现 5 HT综合征 ,共同表现意识模糊、肌张力增高、反应迟钝、主动性减退、震颤、遗忘 ,停药才消失 ,其中 1例曾误诊为老年性痴呆 ;另 143例中失眠、头痛(头晕 )、烦躁等不良反应 ,氟西汀组高于其他 2组 ,余无差异 ,此类不良反应能自行减轻或消失。结论 :应提高对SSRIs药物不良反应的认识 ,对 5 HT综合征要与原有抑郁症状加重仔细鉴别     

SSRIs与三环类抗抑郁药的相互作用及5-羟色胺综合征

据近期《Prescriber Update》报道,选择性5-羟色胺再摄取抑制剂(SSRIs)和抗抑郁药[tricycle antidepressant(TCA)]联用可发生相互作用,使TCA血浆浓度升高2～4倍,导致毒性反应。其发生机理为:SSRIs抑制细胞色素CYP2D6酶,使TCA代谢降低,造成TCA蓄积。临床症状有:便秘、排尿困难、癫痫发作、谵妄以及5-羟色胺综合征。SSRIs和TCA单独应用也可引起5-羟色胺综合征,但两药联用可使危险性加大。因此,该两药联用时,TCA应减量,并应加强监测TCA的毒性反应和5-羟色胺综合征。一旦出现5-羟色胺综合征应立即停药,并予以支持治疗。SSRIs…     

研究发现抗抑郁药与多数出生缺陷无关

2项新的病例对照研究发现，孕妇使用5-羟色胺再摄取抑制剂类抗抑郁药（SSRIs），尽管个别药品【包括舍曲林（sertraline）、帕罗西汀（paroxetin）】可增加罕见畸形的发生风险，但该类药总体出生缺陷及心脏异常风险并未升高。     

国外信息

胺碘酮因毒性反应仅限用于心律失常重症患者经美国FD A建议,惠氏医药公司要求医务人员对所有服用胺碘酮(am iodarone,CO R D A R O N E)片剂的患者作医学指导。胺碘酮为抗心律失常药,毒性大,其不良反应严重,甚至致命,仅适合危及生命的心律失常重症患者。医务人员需向患者提供这些信息,讲明什么情况下不宜服用,同时,患者需如实告知既往有关病史。选择性5-羟色胺再摄取抑制剂(SSRIs)对新生儿潜在的不良作用Emilio等利用WHO全球ADR报告数据库,调查SSRIs的有关不良反应,著文“孕妇服用SSRIs和新生儿停药综合征:数据库分析”,发表于…     

WHO全球药物不良反应信息(12)

母亲应用 5 羟色胺再摄取抑制药 (SSRIs)引起新生儿的ADR母亲在孕期或产后由于胎儿在宫内暴露于SSRIs后的撤药反应 ,或从母乳内摄入SSRIs的毒性反应 ,从而引起新生儿的ADR。澳大利亚ADRAC已收到 2 6例新生儿由于母亲孕期服用SSRIs(帕罗西汀 10例 ,舍曲林 7例 ,氟西汀 7例 ,西酞普兰 2例 )在出生后发生撤药综合征。其症状包括抽搐、震颤、发热及呼吸道症状 (呼吸抑制、窒息及呼吸急促 )。发病时间为出生后 0～ 4d ,多在出生当天发生 ,而在2～ 3d后症状消失。 2 6例撤药综合征中 ,精神激动 /紧张15例 ,喂食不足 7例 ,肌张力减退 7…     

WHO全球药物不良反应信息(31)

5-羟色胺再摄取抑制药（SSRIs）孕妇应用警戒；5-HT或NA再摄取抑制药（SSRIs或SNRIs）与治偏头痛药联用可致命；泰利霉素（telithromycin）新安全信息；替哌那韦（tipranavir）致颅内出血报告；文拉法辛（venlafaxine）过量服用引起的副作用信息。     

帕罗西汀引起致命性低钠血症1例

帕罗西汀(paroxetine)是新的抗抑郁药,属选择性5-羟色胺再摄取抑制剂(SSRIs).这类药物选择性抑制5-羟色胺(5-HT)突触前再摄取而不影响去甲肾上腺素和其它神经递质的摄取.由于不良反应不严重及过量服用的安全性因而在临床广泛使用.低钠血症是SSRIs的一种不常见并发症,一般见于老年患者,表现为抗利尿激素分泌异常综合征(SIADH),虽然许多报道提及氟西汀(fluoxetine)可引起SIADH,但也有帕罗西汀偶可引起SIADH的报道.本文描述1例.     

3种选择性5-羟色胺再摄取抑制药代谢性相互作用的处方分析

目的 了解选择性5-羟色胺再摄取抑制药(SSRIs)氟西汀、舍曲林和帕罗西汀的合并用药情况,为临床合理用药提供参考. 方法 以代谢酶学为指导,从代谢性相互作用的角度对处方进行回顾性分析. 结果3种SSRIs的处方总量为1 985张,其中氟西汀并用CYP2C19抑制药或底物的处方9张,氟西汀、舍曲林和帕罗西汀并用CYP2D6底物或抑制药的处方分别为16,15和12张,氟西汀和舍曲林并用CYP3A4底物或抑制药的处方分别为69张和48张. 结论 避免与已有文献报道能抑制SSRIs代谢的药物合用,或选择无或很少相互作用的同类药物. 药师在SSRIs合并用药中应做好处方审查和患者用药教育,必要时对某些可疑相互作用药进行血药浓度监测.     

5-羟色胺再摄取抑制剂(SSRIs)副作用的深入比较

药物副作用是影响患者生活质量及治疗依从性进而影响疗效的重要因素之一。5-羟色胺再摄取抑制剂（SSRIs）疗效与三环类（TCAs）及单胺氧化酶抑制剂类（MAOIs）抗抑郁药相当，而副作用较轻进而逐步取代TCAs和MOAIs成为抗抑郁治疗的一线药。目前上市的SSRIs共5个药：氟西汀（fluoxetine）、帕罗西汀（paroxetine）、舍曲林（settraline）、氟伏沙明（fluvoxamine）、西酞普兰（citalopram）。它们结构各异（见图1）、与体内多种受体亲和力及活性不完全相同，因此在副作用方面也存在差异，本文通过文献检索回顾大样本有对照研究的文献，对SSRIs的副作用进行深入比较。     

WHO《Signal》药物不良反应选载(7)

选择性5-羟色胺再摄取抑制剂引起高血压反应过去,英国医学会(UMC)发布的药物信息中 并未提及选择性5-羟色胺再摄取抑制剂(SSRIs)会引起高血压的不良反应.然而,美国1999出版的<医师案头参考>(PDR)中已经提到氟西汀和帕罗西汀常常会引起高血压.迄今,UMC已经收到了785份使用SSRIs期间引起高血压的报告(见表1).     

Antidepressants and risk of upper gastrointestinal bleeding

Selective serotonin reuptake inhibitors (SSRIs) are nowadays the most widely used antidepressants in the world, mainly because they have a better adverse reaction profile and a higher safety margin in overdoses, when compared to other antidepressants. These drugs recently have been the target of important debates concerning safety issues, among them the possibility that they may increase the risk of bleeding. Over the 1990s, an increasing number of individual cases of bleeding disorders were reported in the literature and to the pharmacovigilance programmes which prompted several epidemiological and pharmacological studies. In this review we have examined all available data. The whole evidence supports the hypothesis that antidepressants with a relevant blockade action on serotonin reuptake mechanism increase the risk of bleeding. Such disorders may have different degrees of severity and may be located anywhere in the body. The epidemiological evidence is, however, more robust for upper gastrointestinal bleeding. It has been estimated that upper gastrointestinal bleeding may occur at a frequency ranging from 1 in 100 to 1 in 1,000 patient-years of exposure to high-affinity drugs (the SSRIs), with the very old patients being in the highest part of the range. The increased risk may be of particular relevance when the SSRIs are associated with NSAIDs as well as low-dose aspirin.     

Tolerability of selective serotonin reuptake inhibitors: issues relevant to the elderly

Selective serotonin reuptake inhibitors (SSRIs) continue to be the first-choice antidepressant treatment for the elderly as they have similar efficacy to other antidepressants but better tolerability. However, recent concerns have emerged regarding a range of adverse effects that are more likely to occur in the elderly. In part this relates to the increased risk of drug interactions. Platelet dysfunction induced by SSRIs with high serotenergic activity is associated with gastrointestinal bleeding in the first month of treatment, although the overall evidence is weak. The risk of falls and fractures in elderly patients taking SSRIs is similar to that reported with use of tricyclic antidepressants. Hyponatraemia due to induction of the syndrome of inappropriate antidiuretic hormone secretion may be life threatening in the elderly but in most cases is asymptomatic and reversible. Extrapyramidal disorders such as parkinsonism and dyskinesias are more common in the elderly but are rare. There is a very low risk of cerebrovascular adverse reactions in patients taking SSRIs. There are inconsistent findings linking SSRIs with suicidal behaviour in late life and with the risk of cancer. Most of the newly identified adverse effects are either relatively uncommon or of debatable significance. Few differences have been identified among the SSRIs that are of clinical significance. However, it is recommended in the elderly that SSRIs should be titrated slowly to recommended therapeutic doses and used cautiously with other agents known to have the potential for drug interactions.     

Withdrawal Syndrome Following Discontinuation of 28 Antidepressants: Pharmacovigilance Analysis of 31,688 Reports from the WHO Spontaneous Reporting Database

Introduction

Evidence is lacking on withdrawal syndrome related to individual antidepressants and relevant risk factors for severe reactions.

Objective

To ascertain whether antidepressants are associated with an increased reporting of withdrawal syndrome as compared with other medications, and to investigate risk factors for severe reactions.

Methods

This is a case/non-case pharmacovigilance study, based on the VigiBase^®, the WHO global database of individual case safety reports of suspected adverse drug reactions. We performed a disproportionality analysis of reports of antidepressant-related withdrawal syndrome (calculating reporting odds ratio [ROR] and Bayesian information component [IC]). We compared antidepressants to all other drugs, to buprenorphine (positive control), and to each other within each class of antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclics and other antidepressants). Antidepressants with significant disproportionate reporting were ranked in terms of clinical priority. Serious versus non-serious reactions were compared.

Results

There were 31,688 reports of antidepressant-related withdrawal syndrome were found. A disproportionate reporting was detected for 23 antidepressants. The estimated ROR for antidepressants altogether, compared to all other drugs, was 14.26 (95% CI 14.08–14.45), 17.01 for other antidepressants (95% CI 16.73–17.29), 13.65 for SSRIs (95% CI 13.41–13.90) and 2.8 for tricyclics (95% CI 2.59–3.02). Based on clinical priority ranking, the strongest disproportionate reporting was found for paroxetine, duloxetine, venlafaxine and desvenlafaxine, being comparable to buprenorphine. Withdrawal syndrome was reported as severe more often in males, adolescents, persons in polypharmacy, and with a longer antidepressant treatment duration (p < 0.05).

Conclusions

Antidepressants are associated with an increased reporting of withdrawal syndrome compared with other drug classes. When prescribing and discontinuing antidepressants, clinicians should be aware of the potentially different proclivity of withdrawal syndrome across individual antidepressants, and the liability to experience more severe withdrawal symptoms in relation to specific patient characteristics.

     

Treating mood disorders during pregnancy: safety considerations.

Mood disorders in pregnancy may have a negative effect on self care and pregnancy outcome that affects the mother directly and the child indirectly. Thus, some women may require pharmacological treatment. Pharmacotherapy of mood disorders during pregnancy implies specific considerations.This paper presents an updated review of available studies on the treatment of mood disorders and present knowledge on teratogenicity, neonatal effects and long-term neurobehavioural effects for the different psychotropic drugs, including treatment with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), other antidepressants, benzodiazepines, lithium, carbamazepine/valproic acid, lamotrigine and novel antipsychotics. However, the existing knowledge on the use of antidepressants and mood stabilising agents during pregnancy is hampered by a lack of results from randomised controlled trials.SSRIs and TCAs have not been associated with an increased risk of major malformations, but poor neonatal adaptation has been described. Benzodiazepines used in the first trimester have been associated with orofacial clefts. Mood stabilisers such as lithium, carbamazepine and valproic acid (sodium valproate) are associated with an increased risk of fetal malformations. Both benzodiazepines and lithium may cause adaptation problems in the newborn. In utero exposure to novel antipsychotics has not been associated with congenital malformations; however, the data are still limited. The knowledge about long-term neurobehavioural effects in the offspring is still limited for all agents and requires further investigation. Possible adverse effects of fetal exposure must be balanced against the adverse effects of an untreated maternal mood disorder.     

Safety of newer antidepressants in pregnancy

Pharmacotherapy for depression is often necessary during pregnancy. The information available about use of the newer antidepressants in pregnant women is limited by trial design and lack of long-term follow-up of exposed infants. Selective serotonin reuptake inhibitors (SSRIs) are not generally thought to be major teratogens. Some recent studies, however, have suggested that paroxetine may be associated with a small increase in risk of congenital abnormalities, particularly cardiac defects. Data on the effect of SSRIs on the incidence of preterm birth, spontaneous abortion, and fetal death are conflicting. Third-trimester exposure to newer antidepressants, including SSRIs and serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), has been associated with a poor neonatal adaptation syndrome. In addition, SSRI use may be associated with an increased risk of persistent pulmonary hypertension of the newborn. Preliminary evidence suggests that SSRI exposure in utero does not have significant long-term effects on cognition or behavior. Based on limited information, mirtazapine, bupropion, and venlafaxine do not appear to be major teratogens. Little or no information is available on duloxetine.     

Safety of selective serotonin reuptake inhibitors in pregnancy

Psychiatric treatment with selective serotonin reuptake inhibitors (SSRIs) may be desirable or necessary during pregnancy; however, the benefit of these treatments must balance the benefits to the mother with any risk to the developing foetus. At the present time, the role of serotonin in normal central nervous system development, as well as the effects of altering serotonin transmission at critical periods of embryo development, remains to be further clarified. Depression has a high prevalence in pregnant women (around 10%) and approximately one-half of the pregnancies are unplanned, making necessary that physicians have to know the risks associated with the decision to use this kind of antidepressants during pregnancy. The effects of antidepressants in pregnancy could be classified in several main categories: the teratogenic possible effects; the effects on the normal development of the brain and neuropsychological functions; the effects on birth weight and/or early delivery; the risk of increased bleeding on the mother during delivery; the neuropsychological behaviour and adaptation after delivery, including not only neonatal withdrawal syndromes but also pain reactivity and increased parasympathetic cardiac modulation during recovery after an acute noxious event and in a wide range of neurobehavioural outcomes; and medium- to long-term effects in neurocognitive functions in those children. These areas are reviewed according to the most recent published cohort-controlled studies and prospective surveys regarding SSRIs use in pregnancy. The review tries to clarify the blurred aspects of the use of SSRI during pregnancy and to give sensible and up-to-dated guidelines for the treatment of psychiatric disorders with SSRI during pregnancy.     

Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients

Among the antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are often preferred to other classes of antidepressants in the treatment of depression in the elderly because of their better safety profile. Most of the known effects of SSRIs, either beneficial or adverse, are linked to their inhibitory action on the serotonin reuptake transporter (5-HTT). This reuptake mechanism is present not only in neurons but also in other cells such as platelets. Serotoninergic mechanisms seem to play an important role in haemostasis, and their importance in this regard has long been underestimated. Abnormal activation may lead to a pro-thrombotic state, as may occur in patients with major depressive disorder, whilst downregulation, as occurs in patients treated with SSRIs, may have two clinical consequences, both of particular interest in the elderly. On the one hand, there may be an increased risk of bleeding; on the other hand, a reduction in thrombotic risk may be possible. Polymorphism in the promoter region of the gene that transcribes the 5-HTT has been shown to have a relevant impact on its function and, in turn, on the beneficial and adverse effects of SSRIs. Bleeding has been a concern since the introduction of SSRIs, with multiple case reports published and communicated to the pharmacovigilance systems. The first epidemiological study was published in 1999 and since then, 34 epidemiological studies from different areas, most of them including elderly patients in their study populations, have been published with a variety of results. Broadly, the epidemiological evidence supports a moderately increased risk of bleeding associated with the use of SSRIs, which may be critically dependent on patient susceptibility and the presence of risk factors. The impairment of primary haemostasis induced by SSRIs may result, as a beneficial counterpart, in a reduction in the thrombotic risk. A small number of clinical trials and an increasing number of epidemiological studies that include elderly patients have been conducted to clarify whether SSRIs reduce the risk of primary and secondary ischaemic disorders. However, the results have been inconclusive with some studies suggesting a preventive effect and others no effect or even an increased risk. Behind such contradictory results may be the role of depression itself as a cardiovascular risk factor and, therefore, a major confounding factor. How to disentangle its effect from that of the antidepressants is the methodological challenge to be overcome in future studies. In this complex scenario, the elderly seem to be at a crossroads, because they are the group in which both the risks and the benefits can be the greatest. Studies performed to date have provided us with some clues that can help orient clinicians in taking the most appropriate course of action. For instance, as the gastrointestinal bleeding risk appears to increase with age, prudent advice in patients with a previous history of upper-gastrointestinal bleeding or peptic ulcer, and in those who take NSAIDs, oral anticoagulants, antiplatelet drugs or corticosteroids, would be to suggest addition of an acid-suppressing agent to the drug regimen in those elderly patients in whom SSRIs are indicated.     

Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry.

A significant fraction of infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) during late pregnancy display clear signs of antidepressant withdrawal indicating that these drugs can penetrate fetal brain in utero at biologically significant levels. Previous studies in rodents have demonstrated that early exposure to some antidepressants can result in persistent abnormalities in adult behavior and indices of monoaminergic activity. Here, we show that chronic neonatal (postnatal days 8-21) exposure to citalopram (5 mg/kg, twice daily, s.c.), a potent and highly selective SSRI, results in profound reductions in both the rate-limiting serotonin synthetic enzyme (tryptophan hydroxylase) in dorsal raphe and in serotonin transporter expression in cortex that persist into adulthood. Furthermore, neonatal exposure to citalopram produces selective changes in behavior in adult rats including increased locomotor activity and decreased sexual behavior similar to that previously reported for antidepressants that are nonselective monoamine transport inhibitors. These data indicate that the previously reported neurobehavioral effects of antidepressants are a consequence of their effects on the serotonin transporter. Moreover, these data argue that exposure to SSRIs at an early age can disrupt the normal maturation of the serotonin system and alter serotonin-dependent neuronal processes. It is not known whether this effect of SSRIs is paralleled in humans; however, these data suggest that in utero, exposure to SSRIs may have unforeseen long-term neurobehavioral consequences.     

Efficacy, safety and tolerability of combined administration of lithium and selective serotonin reuptake inhibitors: a review of the current evidence. Hertfordshire Neuroscience Research Group

Several case reports have engendered concern about the safety of coadministering lithium and selective serotonin reuptake inhibitor (SSRI) antidepressants and there are theoretical reasons to suppose that lithium and serotonergic antidepressants may be associated with dangerous interactions. Systematic reports regarding combination therapy with lithium and SSRI antidepressants were assimilated for the purpose of this review. Although there are many publications, few are directly informative as to safety and tolerability. A total of 503 patients are considered in systematic reports and, among these, no serious or life-threatening adverse events can be identified. Such data as there are demonstrate little potential for toxic interactions between lithium and SSRIs, although new, non-serious, adverse events do frequently arise. The evidence for the efficacy of addition of lithium to SSRIs in treatment refractory depression is only provisional.     

Non-puerperal lactation associated with antidepressant drug use

Aims The aim of the present study was to estimate the relative risk of non-puerperal lactation in patients using antidepressants in general, and specifically for serotonergic (selective serotonin reuptake inhibitors (SSRIs) and clomipramine) and non-serotonergic antidepressants.
Methods All suspected adverse drug reactions in women and reported from January 1986 until August 1996 to the Netherlands Pharmacovigilance Foundation, a spontaneous adverse drug reaction reporting programme, were analysed. Adverse drug reaction (ADR) reporting odds ratios, defined as the ratio of the exposure odds among reported cases of non-puerperal lactation to the exposure odds of reported other ADRs, were calculated adjusted for age and year of reporting.
Results Thirty-eight cases of non-puerperal lactation were reported, of which 15 were associated with the use of antidepressant drugs. In general, antidepressants were associated with a higher risk of non-puerperal lactation in comparison with other drugs (ADR reporting odds ratio 8.3 [ 95%CI: 4.3–16.1]). Serotonergic antidepressants (selective serotonin reuptake inhibitors (SSRIs) and clomipramine) were associated with a higher risk (OR 12.7 [95%CI: 6.4–25.4]), whereas other antidepressants were not (OR 1.6 [95%CI: 0.2–11.6]), compared with all other drugs.
Conclusions Our results indicate that serotonergic antidepressants are associated with an approximately eight times higher risk of non-puerperal lactation compared with other antidepressants. This effect is probably mediated by an indirect inhibition effect of serotonin on the dopaminergic transmission. This finding is in line with the occurrence of other antidopaminergic effects, such as extrapyramidal symptoms, in patients using serotonergic antidepressants.