Serotonin transporter occupancy in rats exposed to serotonin reuptake inhibitors in utero or via breast milk

Rigorous data regarding fetal central nervous system (CNS) exposure after antidepressant exposure are sparse. The magnitude of serotonin reuptake inhibitor (SRI) CNS exposure was measured in three groups of rats using ex vivo autoradiography of the serotonin transporter (SERT): 1) in utero, 2) postnatal clearance after birth, and 3) exposure through lactation. Rats were exposed to one of five SRI-type antidepressants (escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine) administered continuously via osmotic minipumps to pregnant or nursing dams. Dam dosing was adjusted to reflect the 50th and 85th percentiles of serum concentrations observed in pregnant women. Embryonic day 21 rat pups exposed in utero exhibited >80% SERT occupancy in brain tissue, which is equivalent to that of the pregnant dam and similar to that reported for human pharmacotherapy. Venlafaxine was the exception with occupancies ranging from 61 to 92% across different litters. The magnitude of SERT occupancy is essentially equivalent between dams and fetuses. By postnatal day 4, high SERT occupancy was observed only in fluoxetine-exposed pups (41-92% occupancy). Significantly less, but measurable, exposure occurred via breast milk exposure even in the absence of detectable drug concentrations in nursing pup sera. Pups exposed to SRIs via breast milk for 3 or 7 days exhibited varying SERT occupancies (0-57% depending on the individual medication and dam dose). These data highlight the need for animal modeling of fetal and nursing infant drug exposure using clinically meaningful dosing strategies and appropriate CNS measures to develop rational treatment guidelines that systematically minimize fetal and neonatal medication exposure in humans.     

中国人群5-羟色胺转运蛋白基因多态性与抑郁症及5-羟色胺摄取抑制剂类抗抑郁药治疗效果的关系

背景：研究发现在大脑中与情感和行为有关的皮质和边缘区域5-羟色胺转运蛋白的表达特别丰富.调节5-羟色胺能神经反应的强度和持久性改变大脑5-羟色胺能神经传递,同时5-羟色胺转运蛋白也是5-羟色胺摄取抑制剂的重要靶标.目的：观察南京地区人群中5-羟色胺转运蛋白基因多态性与血浆5-羟色胺浓度及5-羟色胺摄取抑制剂的临床疗效是否存在相关性.设计：病例-对照观察.单位：南京医科大学脑科医院精神科.对象：于2001-01/2003-12选择南京医科大学脑科医院精神科住院的抑郁症患者132例和健康志愿献血者100例作为观察对象.方法：采用聚合酶链式反应多态性分析技术对抑郁症患者和健康者进行基因型分析;采用高效液相电化学法分析血浆中5-羟色胺浓度;用汉密顿抑郁量表评定抗抑郁药的疗效.主要观察指标：两组5-羟色胺转运蛋白基因型频率和等位基因频率分析结果,5-羟色胺转运蛋白基因型与5-羟色胺摄取抑制剂治疗前后血浆5-羟色胺浓度的关系.结果：132例抑郁症患者和100例正常健康者均采集到血样,并完成量表测试,全部进入结果分析.①抑郁症5-羟色胺转运蛋白基因基因型频率与正常对照组基因型频率比较差异无显著性,[（LL 24.2%,LS 44.7%,SS 31.1%）,（LL 29.0%,LS 47.0%,SS 24.0%）,x^2=1.4058,P＞0.05];等位基因频率与正常对照组比较差异无显著性[（L 46.59%,S 53.41%）,（L 52.5%,S47.5%）,x^2=0.696 2,P＞0.05].②不同基因型抑郁症患者治疗前汉密顿抑郁量表总分差异有显著性（F=6.48,P=0.002 1）;经4周5-羟色胺摄取抑制剂类抗抑郁药治疗后,汉密顿抑郁量表总分均显著下降,减分值差异有显著性（F=3.38,P=0.037）.③治疗前不同基因型患者5-羟色胺浓度差异有显著性（F=5.38,P=0.005 7）;4周治疗后,血浆中5-羟色胺浓度均升高,不同基因型的增高值差异有显著性（F=23.55,P＜0.01）.结论：南京地区人群中5-羟色胺转运蛋白基因多态性与抑郁症的发病不存在相关性,但与抑郁症疾病严重程度和5-羟色胺摄取抑制剂治疗效应存在显著的相关性,这一区域的基因型可能成为抑郁症患者实现个体化治疗的一个参考指标.     

中国人群5-羟色胺转运蛋白基因多态性与抑郁症及5-羟色胺摄取抑制剂类抗抑郁药治疗效果的关系

背景:研究发现在大脑中与情感和行为有关的皮质和边缘区域5-羟色胺转运蛋白的表达特别丰富。调节5-羟色胺能神经反应的强度和持久性改变大脑5-羟色胺能神经传递,同时5-羟色胺转运蛋白也是5-羟色胺摄取抑制剂的重要靶标。目的:观察南京地区人群中5-羟色胺转运蛋白基因多态性与血浆5-羟色胺浓度及5-羟色胺摄取抑制剂的临床疗效是否存在相关性。设计:病例-对照观察。单位:南京医科大学脑科医院精神科。对象:于2001-01/2003-12选择南京医科大学脑科医院精神科住院的抑郁症患者132例和健康志愿献血者100例作为观察对象。方法:采用聚合酶链式反应多态性分析技术对抑郁症患者和健康者进行基因型分析;采用高效液相电化学法分析血浆中5-羟色胺浓度;用汉密顿抑郁量表评定抗抑郁药的疗效。主要观察指标:两组5-羟色胺转运蛋白基因型频率和等位基因频率分析结果,5-羟色胺转运蛋白基因型与5-羟色胺摄取抑制剂治疗前后血浆5-羟色胺浓度的关系。结果:132例抑郁症患者和100例正常健康者均采集到血样,并完成量表测试,全部进入结果分析。①抑郁症5-羟色胺转运蛋白基因基因型频率与正常对照组基因型频率比较差异无显著性,[(LL24.2%,LS44.7%,SS31.1%),(LL29.0%,LS47.0%,SS24.0%),χ2=1.4058,P>0.05];等位基因频率与正常对照组比较差异无显著性[(L46.59%,S53.41%),(L52.5%,S47.5%),χ2=0.6962,P>0.05]。②不同基因型抑郁症患者治疗前汉密顿抑郁量表总分差异有显著性(F=6.48,P=0.0021);经4周5-羟色胺摄取抑制剂类抗抑郁药治疗后,汉密顿抑郁量表总分均显著下降,减分值差异有显著性(F=3.38,P=0.037)。③治疗前不同基因型患者5-羟色胺浓度差异有显著性(F=5.38,P=0.0057);4周治疗后,血浆中5-羟色胺浓度均升高,不同基因型的增高值差异有显著性(F=23.55,P<0.01)。结论:南京地区人群中5-羟色胺转运蛋白基因多态性与抑郁症的发病不存在相关性,但与抑郁症疾病严重程度和5-羟色胺摄取抑制剂治疗效应存在显著的相关性,这一区域的基因型可能成为抑郁症患者实现个体化治疗的一个参考指标。     

Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism

Summary. Background: Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased bleeding tendency. Objectives: To prospectively quantify the dose‐response effects of paroxetine and the influence of the serotonin transporter gene (SLC6A4) promoter polymorphism (5‐HTTLPR) on platelet function. Methods: Nineteen drug‐free psychiatric outpatients (44.5 ± 10.8 years) were tested before and after 6 weeks of paroxetine treatment (20 mg day^?1). Based on clinical symptoms, paroxetine dosages were increased (40–50 mg day^?1) for 6 more weeks in 11 patients. Parameters related to platelet function were assessed by bleeding time, platelet function analyzer (PFA), platelet serotonin, platelet factor 4 (PF4), β‐thromboglobulin (β‐TG), and aggregation tests. Results: Paroxetine 20 mg day^?1 increased mean bleeding time by 1.2 min (95% confidence interval (95% CI) ?0.2–2.7) and reduced median platelet serotonin level (463 ng 10^?9 platelets; inter quartile range (IQR) 361–666), and platelet ß‐TG concentration (3.1 IU 10^?6 platelets; IQR 0.3–6.0). Other platelet parameters did not change significantly. Serial platelet aggregation tests did not become abnormal. Paroxetine dose‐escalation did not further influence platelet function. However, 5‐HTTLPR polymorphisms modified these effects: in L_A/L_A‐carriers, bleeding times did not change (?0.2 min; 95% CI ?0.6 to 0.9), while bleeding times significantly increased in <2L_A‐allele carriers (2.3 min; 95% CI 0.5 to 4.07; P = 0.032). Platelet serotonin decreases were larger in patients without L_A‐alleles (868 ng 10^?9 platelets; IQR 585 to 1213) than in ≥1 L_A‐allele carriers (457 ng 10^?9 platelets; IQR 392 to 598; P = 0.035). PFA closure time and PF4 increased significantly in patients without L_A‐alleles. Conclusions: Paroxetine 20 mg day^?1 does not increase overall bleeding time, but impairs platelet function by decreasing the levels of platelet serotonin and platelet ß‐TG. These paroxetine effects appear to be mediated by 5‐HTTLPR, with most pronounced effects in patients without L_A‐alleles.     

Hyponatremia as a complication of selective serotonin reuptake inhibitors

PURPOSE: To review the literature on hyponatremia as a complication of selective serotonin reuptake inhibitors (SSRIs) in the elderly; to summarize the prevalence, clinical findings, treatment modalities, and likely pathophysiological mechanisms related to the problem. DATA SOURCES: All published articles that could be located since Food and Drug Administration approval of this class of medications in 1987, using MEDLINE, CINAHL, and PsychInfo databases and a case study. CONCLUSIONS: Hyponatremia is a potentially serious complication of the use of SSRIs and is statistically more prevalent in the elderly and in females. Few clinical guidelines exist for managing this potential reaction. No evidence-based guidelines could be located. IMPLICATIONS FOR PRACTICE: Since articles describing this phenomenon have been primarily case studies, many healthcare providers may not be aware of this potentially serious complication. Monitoring of serum sodium in elderly female patients starting SSRI therapy seems prudent.     

Selective serotonin reuptake inhibitor discontinuation syndrome: a review

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed in the treatment of depression and anxiety, as well as obsessive-compulsive, eating, and impulse-control disorders. Paralleling their widespread use has been an increase in adverse-effect reports not noted during short-term efficacy studies. Significant among these adverse effects is SSRI discontinuation syndrome, which follows the interruption of extended treatment or a reduction in drug dosage and entails somatic and psychological symptoms. These self-limiting symptoms resolve on reintroduction of the drug and cannot be explained as a remanifestation of the original disorder. To facilitate proper diagnosis and avoid unnecessary therapeutic or diagnostic interventions, all physicians who prescribe SSRIs should become familiar with these symptoms. The most appropriate approach to therapy for discontinuation syndrome involves educating patients and reassuring them that this is a reversible condition, reinstating the original SSRI, and further slowing the rate of tapering.     

The selective serotonin reuptake inhibitor citalopram induces the storage of serotonin in catecholaminergic terminals

We investigated whether selective inhibition of serotonin (5-hydroxytryptamine; 5-HT) transporter with citalopram leads to accumulation of 5-HT in catecholaminergic neurons. In the rabbit olfactory tubercle, citalopram (1-10 microM) inhibited [(3)H]5-HT uptake; however, the maximal degree of inhibition achieved was 70%. Addition of nomifensine (1-10 microM) was required for complete inhibition of [(3)H]5-HT uptake. In slices labeled with 0.1 microM [(3)H]5-HT, cold 5-HT (0.03-1 microM) induced a large increase in the efflux (release) of stored [(3)H]5-HT, an effect blocked by coperfusion with 1 microM citalopram. Similar concentrations (0.03-1 microM) of norepinephrine (NE) or dopamine (DA) failed to release [(3)H]5-HT. When labeling with 0.1 microM [(3)H]5-HT was carried out in the presence of citalopram, 1) low concentrations of 5-HT failed to release [(3)H]5-HT; 2) DA and NE were more potent and effective in releasing [(3)H]5-HT than in control slices; 3) coperfusion of NE, DA, or 5-HT with citalopram enhanced the release of [(3)H]5-HT induced by the catecholamines but not by 5-HT; and 4) coperfusion of NE or DA with nomifensine antagonized NE- and DA-evoked [(3)H]5-HT release, with a greater effect on NE than on DA. These results suggest that in the rabbit olfactory tubercle, where there is coexistence of 5-HT, NE, and DA neurons, inhibition of the 5-HT transporter led to accumulation of 5-HT in catecholaminergic terminals. Thus, during treatment with selective serotonin uptake inhibitors (SSRIs), 5-HT may be stored in catecholaminergic neurons acting as a false neurotransmitter and/or affecting the disposition of DA and/or NE. Transmitter relocation may be involved in the antidepressant action of SSRIs.     

Selective serotonin reuptake inhibitors (SSRIs) in pregnancy: a review

Major affective disorders including depression and anxiety occur commonly in women of childbearing age and their incidence can increase during and after pregnancy. There is a critical clinical demand for treatment of these disorders, but the balance between treating affective disorders without harming the developing fetus is a difficult one. This has created concern both among women planning pregnancies, and those women who are pregnant already, as well as among families and healthcare providers. Currently, selective serotonin reuptake inhibitors (SSRIs) are the drugs of choice for the treatment of these disorders in pregnant women because of their documented efficacy and mild side effect profile. There is some research concerning SSRI use and pregnancy, which is the focus of this article.     

Treating depression with selective serotonin reuptake inhibitors: a practical approach.

Depression is a common disorder that is becoming better understood as an illness that can be chronic, recurrent, and refractory to treatment. Depression can produce substantial suffering and profoundly affect a patient's self-esteem, relationships, and functional capacity. The improved adverse-effect profile and safety from overdose of selective serotonin reuptake inhibitors (SSRIs) have led to treatment of milder forms of depression and thus increased treatment of depression overall. This article synthesizes several previously published reviews and psychopharmacology resources and addresses practical issues related to initiating, monitoring, continuing, and discontinuing SSRIs. Precautions related to SSRI use and important considerations for various types of depression are discussed.     

选择性5羟色胺抑制剂减轻中风后残障评分的荟萃分析

目的分析选择性5羟色胺摄取抑制剂对减轻中风患者残障程度的作用。方法检索Medline、Pub Med、Embase、Wos 1990至2015年相关文献,Jadad评分评估所涉及研究的质量,剔除评分<4分的研究,研究分2组,试验组为使用5羟色胺摄取抑制剂的中风患者,对照组为不使用5羟色胺摄取抑制剂的中风患者,2组患者初次中风90 d时使用Rankin量表评估残障分值;分析选择性5羟色胺摄取抑制剂对中风患者的获益程度。结果相对于中风患者不使用选择性5羟色胺摄取抑制剂,使用者中风患者总评分标准化均数差(SMD)=0.75,95%CI:0.64~0.87,Z=12.67,P=0.000;(1)氟西汀使用者SMD=0.44,95%CI:0.20~0.68,Z=3.55,P=0.000;(2)帕罗西汀使用者分SMD=0.82,95%CI:0.56~1.08,Z=6.20,P=0.000;(3)舍曲林使用者SMD=0.69,95%CI:0.44~0.94,Z=5.42,P=0.00;(4)西酞普兰使用者SMD=0.91,95%CI:0.64~1.17,Z=6.72,P=0.000;(5)艾司西酞普兰使用者SMD=1.05,95%CI:0.75~1.36,Z=6.78,P=0.000。结论选择性5羟色胺摄取抑制剂能明显减轻中风患者残障程度。     

Selective serotonin reuptake inhibitors reduce the attack frequency in familial mediterranean Fever

Familial Mediterranean Fever (FMF) is characterized by recurrent acute attacks of fever and serositis, and colchicine is the primary treatment. The pathogenesis of the disease has not been fully understood. Resistance to colchicine remains to be a problem in up to 30% of the patients and yet there seems to be no alternative treatment. In this study our objective was to investigate whether a selective serotonin re-uptake inhibitor (SSRI) could affect the attack frequency and acute phase response in FMF patients who were unresponsive to colchicine. We retrospectively evaluated the hospital files of 11 colchicine-unresponsive FMF patients who had been treated with SSRIs. According to the records and re-evaluation of the patients, the total number of the FMF attacks was calculated before and after the SSRI, adjunct to colchicine. The laboratory values including erythrocyte sedimentation rate, C-reactive protein, fibrinogen and white blood cell counts were also noted before and after the SSRI treatment from their hospital files. The mean attack frequency before adding SSRI to colchicine was 8.09 +/- 3.53 per 6 months, and at the end of this period there was a great decline in the number of mean attack frequency (0.36 +/- 0.50 attacks per 6 months) (p < 0.001). Acute phase reactants were significantly decreased after SSRI treatment (p < 0.001). All of the colchicine-unresponsive patients had depression and 3 of those patients also had fibromyalgia. SSRIs appear to be useful adjuncts in the management of FMF patients who continue to have attacks despite regular colchicine treatment.     

Antinociceptive properties of fenfluramine, a serotonin reuptake inhibitor, in a rat model of neuropathy

Fenfluramine is an indirect agonist of 5-hydroxytryptamine (5-HT) receptors that acts by evoking 5-HT release and blocking 5-HT reuptake in neuronal cells. The current study compared the antinociceptive properties of fenfluramine with those of the tricyclic antidepressants amitriptyline and desipramine in rat models of acute, persistent, and neuropathic pain. In a rat model of neuropathic pain produced by tight ligation of the L(5)/L(6) spinal nerves, i.v. bolus injection of fenfluramine resulted in a dose-dependent and long-lasting (>4 h) blockade of mechanical allodynia (ED(50) = 3.5 mg/kg; 95% confidence interval, 2.2-5.4 mg/kg) and cold allodynia (ED(50) = 2.4 mg/kg; 95% confidence range, 1.2-4.6 mg/kg). Fenfluramine also prevented tonic pain evoked by the s.c. injection of dilute (5%) formaldehyde solution (formalin), into the dorsal hindpaw. The i.v. administration of amitriptyline (4.7 mg/kg) or desipramine (13.5 mg/kg) at maximum tolerated doses did not block either allodynia in rats with spinal nerve ligation-induced painful neuropathy or tonic pain in the formalin test. Fenfluramine had differential effects on acute behavioral responses to noxious thermal (heat), chemical (5% formaldehyde solution), and mechanical stimuli; it completely inhibited nociceptive behavior in the acute phase of the formaldehyde solution test and partially inhibited licking and jumping responses in the hot-plate test but did not alter nociceptive thresholds in either the paw pressure test or the tail immersion test. Intracerebroventricular bolus injection of 240 microg of fenfluramine significantly increased mechanical allodynia thresholds; however, the same dose administered spinally by intrathecal bolus injection was ineffective. The inhibitory effects of fenfluramine on mechanical allodynia (and tonic pain behavior in the formaldehyde solution test) were prevented by pretreatment with 10 mg/kg metergoline, a selective antagonist of 5-HT receptors, but not with the mu-opioid receptor antagonist naloxone. These results suggest that fenfluramine produces analgesia in the formaldehyde solution test and the spinal nerve ligation model of neuropathic pain by potentiating, at least in part, supraspinal 5-HT mediated processes.     

Susceptibility of the elderly patient to hyponatremia induced by selective serotonin reuptake inhibitors

Numerous spontaneous reports of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have followed the increased use of selective serotonin reuptake inhibitors (SSRI). It has been estimated that 1 in 200 patients treated per year developed SIADH, age and low body weight being particular risk factors. No clear gender effect has been detected when confounding factors such as body weight or antidepressant consumption are taken into account. Age-related susceptibility to hyponatraemia may be explained by physiological changes in renal and endocrine function. The high prevalence of polymedication and pluripathology in the elderly may be a contributing factor as well. To date, no study has demonstrated how SSRIs affect the regulation of fluid/sodium balance nor whether they have an independent effect on this regulation in depressed subjects.     

The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy.

The effect of the selective serotonin reuptake inhibitor citalopram on diabetic neuropathy symptoms was examined in a double-blind, placebo-controlled, crossover study for two 3-week periods. Citalopram was given as a fixed dose of 40 mg/day. Data from 15 patients could be included in the statistical analysis. Citalopram significantly relieved the symptoms of neuropathy as measured by both observer- and self-rating in comparison with placebo. The steady-state plasma concentration of citalopram was 10 to 890 nmol/L. There was no significant relationship between the plasma concentration of citalopram and the effect of treatment as measured by observer- or self-rating. Two of 17 patients, both receiving citalopram, left the study because of side effects (nausea and vomiting or gastric upset and diarrhea). Side-effect ratings were significantly higher during administration of citalopram than during administration of placebo, but citalopram was generally well tolerated. Compared with earlier results obtained with imipramine administered on the basis of plasma level monitoring, citalopram appeared to be less effective, but seemed to be better tolerated.     

A controlled study of a serotonin reuptake blocker, zimelidine, in the treatment of chronic pain

Zimelidine inhibits the central neuronal reuptake of serotonin and has undergone clinical evaluation as an antidepressant. Twenty patients with chronic pain of non-malignant origin (mean duration 15.8 years) were entered into a double blind cross-over study of the analgesic efficacy of zimelidine and placebo. The duration of each treatment phase was 6 weeks and there was a comprehensive assessment of each patient prior to the commencement and at the completion of the study, during a brief period of hospitalisation. Zimelidine was superior (P less than 0.05) to placebo with respect to pain relief based on a global assessment (by the clinical investigators) performed at the completion of each treatment phase. However, there was no significant difference in analgesic efficacy between the zimelidine and placebo treatment phases based on the following criteria: (a) changes in the minimum effective blood concentration of pethidine necessary to provide pain relief in each patient, measured during a pethidine infusion of 1.67 mg/min for 60 min; (b) changes in pain scores estimated by patients using the visual analogue pain scale (VAPS); (c) changes in patients' estimates of pain intensity associated with various daily activities. Significant pain relief was apparent within 2-3 days in those patients who had a beneficial effect, which contrasts with the documented 3-4 weeks for maximal antidepressant effects. The results of this study suggest that serotonin reuptake blockers do not provide consistent pain relief in patients with chronic pain, but may contribute an analgesic effect in the treatment of some patients.     

Serotonin-induced acute desensitization of serotonin2 receptors in human platelets via a mechanism involving protein kinase C

Serotonin (5-HT)-induced changes in the levels of intracellular Ca++ were analyzed in human platelets, using the Ca+(+)-sensitive dye 1-(2-(5'-carboxyoxazol-2'-yl)-6-aminobenzofuran-5-oxy)-2-(2' -amino-5'- methylphenox)-ethane-N,N,N',N'-tetraacetic acid, pentaacetoxymethyl ester, to investigate the regulation of 5-HT2 receptor function. Serotonin mobilized intracellular Ca++ in a dose-dependent fashion from basal level of 98 +/- 2.7 and up to 211 +/- 5.8 nM with an EC50 value for 5-HT of 0.2 microM. Ketanserin, a 5-HT2 antagonist, reversed the 5-HT (10 microM)-induced Ca++ increase in a dose-dependent manner with an IC50 value of 2 nM. An initial treatment with 10 microM 5-HT abolished the response to a second treatment with 100 microM 5-HT, suggesting that 5-HT evoked an acute desensitization of 5-HT2 receptors in human platelets. Mezerein and phorbol 12-myristate 13-acetate, activators of protein kinase C, inhibited 5-HT-stimulated inositol monophosphate accumulation with IC50 values of 3 and 10 nM, respectively. Furthermore, a protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride prevented the protein kinase C activator-induced inhibition against 5-HT-mediated inositol monophosphate accumulation. Mezerein also inhibited 5-HT (10 microM)-mediated Ca++ release with an IC50 value of 3 nM. 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride prevented the inhibition by mezerein of the 5-HT-stimulated Ca++ increase. Moreover, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride by itself enhanced the Ca++ spike induced by 100 microM 5-HT, the plateau phase induced by 10 microM 5-HT and the second response to 5-HT. These findings suggest that 5-HT2 receptor activation mobilizes intracellular Ca++ in human platelets and that this receptor may be desensitized acutely by a protein kinase C mediated feedback system.