Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model

Bone wound healing is a highly dynamic and precisely controlled process through which damaged bone undergoes repair and complete regeneration. External factors can alter this process, leading to delayed or failed bone wound healing. The findings of recent studies suggest that the use of selective serotonin reuptake inhibitors(SSRIs) can reduce bone mass, precipitate osteoporotic fractures and increase the rate of dental implant failure. With 10% of Americans prescribed antidepressants, the potential of SSRIs to impair bone healing may adversely affect millions of patients’ ability to heal after sustaining trauma. Here, we investigate the effect of the SSRI sertraline on bone healing through pre-treatment with(10 mg·kg-1sertraline in drinking water, n = 26) or without(control, n = 30) SSRI followed by the creation of a 5-mm calvarial defect. Animals were randomized into three surgical groups:(a) empty/sham,(b) implanted with a DermaMatrix scaffold soak-loaded with sterile PBS or(c) DermaMatrix soak-loaded with542.5 ng BMP2. SSRI exposure continued until sacrifice in the exposed groups at 4 weeks after surgery. Sertraline exposure resulted in decreased bone healing with significant decreases in trabecular thickness, trabecular number and osteoclast dysfunction while significantly increasing mature collagen fiber formation. These findings indicate that sertraline exposure can impair bone wound healing through disruption of bone repair and regeneration while promoting or defaulting to scar formation within the defect site.

Selective serotonin reuptake inhibitors and Alzheimer’s disease

Given the failure to develop disease-modifying therapies for Alzheimer’s disease(AD),strategies aiming at preventing or delaying the onset of the disease are being prioritized.While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on,a key determining factor may be the timing of depression onset in older adults.There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline.Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden,tau deposits and neurogenesis.In humans,studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors.Paroxetine,which has strong anticholinergic properties,was associated with increased mortality and mixed effects on amyloid and tau deposits in mice,as well as increased odds of developing AD in humans.Although most of the data regarding selective serotonin reuptake inhibitors is promising,findings should be interpreted cautiously because of notable methodological heterogeneity between studies.There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

Relationship between use of selective serotonin reuptake inhibitors and irritable bowel syndrome: A populationbased cohort study

AIM To investigate the relationship between selective serotonin reuptake inhibitor(SSRI)use and the subsequent development of irritable bowel syndrome(IBS).METHODS This retrospective,observational,population-based cohort study collected data from Taiwan’s National Health Insurance Research Database.A total of 19653patients newly using SSRIs and 78612 patients not using SSRIs,matched by age and sex at a ratio of 1:4, were enrolled in the study from January 1,2000 to December 31,2010.The patients were followed until IBS diagnosis,withdrawal from the National Health Insurance system,or the end of 2011.We analyzed the effects of SSRIs on the risk of subsequent IBS using Cox proportional hazards regression models.RESULTS A total of 236 patients in the SSRI cohort(incidence,2.17/1000 person-years)and 478 patients in the comparison cohort(incidence,1.04/1000 person-years)received a new diagnosis of IBS.The mean follow-up period from SSRI exposure to IBS diagnosis was 2.05years.The incidence of IBS increased with advancing age.Patients with anxiety disorders had a significantly increased adjusted hazard ratio(a HR)of IBS(a HR=1.33,95%CI:1.11-1.59,P=0.002).After adjusting for sex,age,urbanization,family income,area of residence,occupation,the use of anti-psychotics and other comorbidities,the overall a HR in the SSRI cohort compared with that in the comparison cohort was1.74(95%CI:1.44-2.10;P<0.001).The cumulative incidence of IBS was higher in the SSRI cohort than in the non-SSRI cohort(log-rank test,P<0.001).CONCLUSION SSRI users show an increased risk of subsequent diagnosis of IBS in Taiwan.

Mouse strain differences in selective serotonin reuptake inhibitors sensitivity correlates with serotonin transporter binding and function

OBJECTIVE Selective serotonin reuptake inhibitors(SSRIs) bind 5-HT transporters,leading to the accumulation of 5-HT and amelioration of depression.Although different mouse strain showed different sensitivity to SSRIs in mouse models of depression,the reason for these strain differences remains unclear.Here,therefore,in the present study,we examined immobility time and locomotor activity in two mouse strains,namely,C57BL/6 J and DBA/2 J mice,and the effects of the SSRIs fluoxetine.Furthermore,we analyzed 5-HT transporter binding and reuptake inhibition in both strains to explore their relationship with the immobility and locomotor activity effects of the three SSRIs in these two mouse strains.METHODS Strain differences in SSRI effects in the tail suspension test(TST) and forced swimming test(FST).To initiate our studies,we sought to confirm that SERT strain variation did not alter SERT protein expression,5-HT recognition,or uptake activity when expressed in C57BL/6 J and DBA/2 J mice.Radioligand binding assays were conducted to determine the affinity of the SSRIs for the 5-HT transporters in the two mouse strains.RESULTS SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2 J but not C57BL/6 J mouse strains,whereas fluoxetine showed opposite results.Paroxetine reduced immobility time similarly in both strains.The affinity of citalopram for the 5-HT transporter in DBA/2 J mice was 700-fold higher than that for in C57BL/6 J mice,whereas the affinity of fluoxetine in C57BL/6 J mice was 100-fold higher than that in the DBA/2 J mouse.Furthermore,High citalopram concentrations were required to [3 H]5-HT uptake in C57BL/6 J but not DBA/2 J mouse cortical synaptosomes,whereas fluoxetine also showed opposite results.CONCLUSION Immobility duration depends on 5-HT transporter binding levels,leading to apparent strain differences in immobility time in FST and TST.Furthermore,differences in 5-HT transporter binding may cause variations in SSRI responses on behaviors.SERT mutation mice maintained sensitivity to paroxetine,an antidepressant that is unaffected by the mouse mutation.Therefore,the background strain of these mice likely contributes to the acute behavioral actions of SSRIs in immobility time.These differences may help to explain some of the discrepancies in studies that used these strains of mice to examine the role of 5-HT in mouse models of depression.Future studies should investigate additional neural substrates and molecular mechanisms underlying strain variations in mouse models of depression to help identify genetic predispositions to this disorder in humans.

Comparison of paroxetine and dapoxetine, a novel selective serotonin reuptake inhibitor in the treatment of premature ejaculation

Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the first drug approved for the on-demand treatment of premature ejaculation （PE）, Our objective in this study was to characterize the efficacy of on-demand dapoxetine （30 and 60 mg） and daily paroxetine （20 mg） usage in treating PE, We conducted a 1 month study involving a total of 150 patients. Patients were divided into three groups of 50, Group 1 were treated with on-demand dapoxetine （30 mg）, Group 2 with on-demand dapoxetine （60 mg） and Group 3 with daily paroxetine （20 rag）, Our outcome measurement was increased from baseline intravaginal ejaculatory latency time （IELT） after treatment, The IELT increased from baseline to posttreatment by 117%, 117% and 170% in the paroxetine group （P 〈 0,01）, 30 mg dapoxetine group （P 〈 0,01） and 60 mg dapoxetine group （P 〈 0.01）, respectively, The increase from baseline IELT were similar for the 30 mg dapoxetine and paroxetine groups （P 〉 0,05）, while the 60 mg dapoxetine group had a larger posttreatment IELT increase compared with the 30 mg dapoxetine （P〈 0.05） and paroxetine （P〈 0.01） groups, Dapoxetine （60 mg） 1-3 h before planned intercourse is a very effective treatment modality for PE. However, an on-demand dose of 30 mg dapoxetine is no more effective than the currently prescribed paroxetine treatment.

The Selective Serotonin Reuptake Inhibitor-Sertraline Diminishes Conspecific Aggression in Male Fighting <i>Betta splendens</i>Fish

In conspecific type of aggression the modulation of 5-hydroxytryptamine (5-HT) plays a main role. A decrease of 5-HT in the brain intensifies this type of aggression and in contrast, the increase of 5-HT reduces it. The aim of this study was to examine the effects of different concentrations of sertraline HCl on aggressive behavior of Betta splendens male fish. It was concluded that sertraline added to aquarium water in the dose of 0.4, 4.0 and/or 100.0 μg·L-1 BW during 14 days of exposition increased synaptic levels of 5-HT which in turn resulted in reduction of specific aggressive behavior in the environmental concentrations (0.4 μg) and then times higher. Sertraline caused a periodic, and sometimes even total weakening of the male-male type fight, which was a standard trial applied in ethological research on the Siamese fighting fish. In the current study, the most effective one is proved to be the dose of 4.0 μg·L-1 BW (parallel to earlier investigated fluoxetine in the same dose).

Does serotonin reuptake inhibitor therapy increase the risk of post-sphincterotomy bleeding in patients undergoing endoscopic retrograde cholangio-pancreatography?

To evaluate the risk of immediate and delayed bleeding following sphincterotomy procedure. METHODSThis retrospective cohort study was conducted with all patients who underwent endoscopic sphincterotomy during January 2006 to September 2015 at a tertiary academic center. Patients were grouped according to pre procedural usage of serotonin reuptake inhibitors (SRIs). Both groups were matched for demographic and clinical characteristics. Patients with thrombocytopenia, increased international normalized ratio, or a history of bleeding or coagulation disorders, concurrent use of other antiplatelet/anticoagulants were excluded from the study. RESULTSA total of 447 patients were included, of which 219 (45.9%) used SRIs and 228 (54.1%) cases did not. There was no significant difference in acute or delayed bleeding during endoscopic sphincterotomy between the two groups. (8.2% vs 12.3%, P = 0.16). CONCLUSIONThe use of SRIs was not associated with an increased risk of post-sphincterotomy bleeding. To our best knowledge, this is the first study to explore this association.

Fluoxetine,a selective serotonin reuptake inhibitor used clinically,improves bladder function in a mouse model of moderate spinal cord injury

After spinal cord injury,the upward conduction of the spinal cord is lost,resulting in the loss of micturition control,which manifests as detrusor sphincter dyssynergia and insufficient micturition.Studies have shown that serotonergic axons play important roles in the control of the descending urination tract.In this study,mouse models of moderate spinal cord contusions were established.The serotonin agonists quipazine(0.2 mg/kg),8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DAPT,0.1 mg/kg),buspirone(1 mg/kg),sumatriptan(1 mg/kg),and rizatriptan(50 mg/kg),the serotonin reuptake inhibitors fluoxetine(20 mg/kg)and duloxetine(1 mg/kg),and the dopamine receptor agonist SKF-82197(0.1 mg/kg)were intraperitoneally administered to the model mice 35 days post-injury in an acute manner.The voided stain on paper method and urodynamics revealed that fluoxetine reduced the amount of residual urine in the bladder and decreased bladder and external urethral sphincter pressure in a mouse model of moderate spinal cord injury.However,fluoxetine did not improve the micturition function in a mouse model of severe spinal cord injury.In contrast,the other serotonergic drugs had no effects on the micturition functions of spinal cord injury model mice.This study was ethically approved by the Institutional Animal Care and Use Committee of Jiangsu Province Hospital of Chinese Medicine(approval No.2020DW-20-02)on September 11,2020.

Exploring a novel class tryptophan hydroxylase 1 inhibitor derived from Sambucus williamsii Hance for the osteoporosis treatment

Objective:Gut-derived serotonin strongly inhibits bone formation by inhibiting osteoblast proliferation.Our previous study demonstrated that the lignan-rich fraction prepared from Sambucus willimasii Hance,a folk herbal medicine used to treat bone fractures and joint diseases in China,exerted bone-protective effects,and its actions were modulated by suppressing the synthesis of gut-derived serotonin via the inhibition of intestinal tryptophan hydroxylase 1(TPH-1).However,there is no direct evidence for the action of lignans on TPH-1.This study aimed to verify the direct action of lignans on the TPH-1 and its influence on serotonin synthesis and bone properties.Methods:Molecular docking and surface plasmon resonance were performed to determine the affinities of lignans to TPH-1.The cell viability and the protein activity and expression of TPH-1 were measured in RBL2H3 cells.The serum serotonin level and bone mineral density upon lignan treatment in ovariectomized mice were determined.Result:The lignans showed high binding scores and binding affinities to TPH-1,inhibited the activity and protein expression of TPH-1,suppressed the serum serotonin levels in ovariectomized mice as well as promoted bone mineral density.Conclusion:This is the first study to report that lignans are novel TPH-1 inhibitors and that these lignans could be potential agents for the management of serotonin-related diseases,including osteoporosis.

Serotonin syndrome controversies:A need for consensus

Serotonin syndrome(SS)is a drug-induced clinical syndrome resulting from increased serotonergic activity in the central nervous system.Although more than seven decades have passed since the first description of SS,it is still an enigma in terms of terminology,clinical features,etiology,pathophysiology,diagnostic criteria,and therapeutic measures.The majority of SS cases have previously been reported by toxicology or psychiatry centers,particularly in people with mental illness.However,serotonergic medications are used for a variety of conditions other than mental illness.Serotonergic properties have been discovered in several new drugs,including over-the-counter medications.These days,cases are reported in non-toxicology centers,such as perioperative settings,neurology clinics,cardiology settings,gynecology settings,and pediatric clinics.Overdoses or poisonings of serotonergic agents constituted the majority of the cases observed in toxicology or psychiatry centers.Overdose or poisoning of serotonergic drugs is uncommon in other clinical settings.Patients may develop SS at therapeutic dosages.Moreover,these patients may continue to use serotonergic medications even if they develop mild to moderate SS due to several reasons.Thus,the clinical presentation(onset,severity,and clinical features)in such instances may not exactly match what toxicologists or psychiatrists observe in their respective settings.They produce considerable diversity in many aspects of SS.However,other experts discount these new developments in SS.Since SS is a potentially lethal illness,consensus is required on several concerns related to SS.

The role of selective serotonin reuptake inhibitors and tricyclic antidepressants in addressing reduction of Meniere's disease burden:A scoping review

Objective:To assess the effect of selective serotonin reuptake inhibitors(SSRIs)and tricyclic antidepressants(TCAs)in reducing vertigo,tinnitus,and hearing loss among patients with Meniere's disease(MD).Data Sources:The following databases were utilized in this scoping review:Ovid Medline,PubMed-NCBI,CINAHL,Cochrane Library,Web of Science,and Clinicaltrials.gov.Method:Studies were identified through the following search phrases:"serotonin specific reuptake inhibitors"OR"tricyclic antidepressants"AND"Meniere's disease."References from included manuscripts were examined for possible inclusion of additional studies.Results:The literature search yielded 23 results,which were screened by three independent reviewers.Seventeen studies and three duplicates were excluded.An examination of references from the included studies yielded two additional publications.A total of four published studies assessing SSRIs and TCAs among 147 patients with MD were ultimately included.Four studies described significant reductions in vertigo attack frequency among patients treated with either SSRIs or TCAs compared to their pretreatment baseline.Three studies assessed the drugs'effects on hearing,of which none found a significant difference among patients treated with SSRIs or TCAs.One study found a significant decrease in patient-reported tinnitus following treatment with TCAs or SSRIs compared to their pretreatment baseline.Conclusions:Data exploring SSRIs and TCAs among patients with MD suggests that these medications may reduce the frequency of tinnitus and vertigo,although there was significant heterogeneity in outcome reporting.There remains a need for larger-scale prospective studies that emphasize objective data to evaluate their effective-ness in reducing common MD symptoms.

Possible association of the 5-HTTLPR serotonin transporter promoter gene polymorphism with premature ejaculation in a Turkish population

We evaluated the genotypes of the serotonin transporter gene （5-HTT） in patients with premature ejaculation （PE） to determine the role of genetic factors in the etiopathogenesis of PE and possibly to identify the patient subgroups. A total of 70 PE patients and 70 controls were included in this study. All men were heterosexual, had no other disorders and were either married or in a stable relationship. PE was defined as ejaculation that occurred within 1 min of vaginal intromission. Genomic DNA from patients and controls was analyzed using polymerase chain reaction, and allelic variations of the promoter region of the serotonin transporter gene （5-HTTLPR） were determined. The 5-HTTLPR （serotonin transporter promoter gene） genotypes in PE patients vs. controls were distributed as follows： L/L 16% vs. 17%, L/S 30% vs. 53% and S/S 54% vs. 28%. We examined the haplotype analysis for three polymorphisms of the 5-HTTLPR gene： LL, LS and SS. The appropriateness of the allele frequencies in the 5-HTTLPR gene was analyzed by the Hardy-Weinberg equilibrium using the Z-test. The short （S） allele of the 5-HTTLPR gene was significantly more frequent in PE patients than in controls （P 〈 0.05）. We suggest that the 5-HTTLPR gene plays a role in the pathophysiology of all primary PE cases. Further studies are needed to evaluate the relationship between 5-HTTLPR gene polymorphism and patient subgroup （such as primary and secondary PE） responses to selective serotonin reuptake inhibitors as well as ethnic differences.

Differences of Plasma Levels of Tryptophan, Serotonin, 5-Hydroxyindole Acetic Acid, and Kynurenine between Healthy People and Patients of Major Monopolar Depression at Various Age and Gender

Background: It is not well analyzed whether there are differences in plasma levels of tryptophan (TRP) metabolites between healthy control people (HC) and patients of major monopolar depression (MMD). Methods: Ultra high-speed liquid chromatography/mass spectrometry has been used for the simultaneous determination of plasma levels of tryptophan metabolites in depressive patients. Results: There are no significant differences between plasma levels of TRP between HC and MMD. Plasma levels of TRP of HC are higher in young men, young women, old men, and old women in this order. Serotonin (5-HT) levels are higher in MMD than HC. Plasma levels of 5-HIAA of HC are also higher than those of patients of MMD. Plasma levels of kynurenine (KYN) of healthy old men and old women are higher than those of young men and old women. Plasma levels of KYN are higher in old women and young men of MMD than those of HC. Conclusion: Plasma levels of 5-HT are higher in patients of MMD than those of HC, which may suggest that use of drugs inhibiting the 5-HT transportation may increase plasma levels of 5-HT in MMD.

CYP2D6、CYP2C19、CYP2B6、SLC6A4、HTR2A基因型和5-羟色胺再摄取抑制剂抗抑郁药:2023年CPIC指南解读

2023年临床药物基因组学实施联盟(CPIC)更新并扩展了2015年CYP2D6和CYP2C19基因型与选择性5-羟色胺再摄取抑制剂(SSRIs)治疗指南,在涉及基因型与药物部分分别增加了CYP2B6、5-羟色胺转运体SLC6A4、5-羟色胺2A受体HTR2A以及5-羟色胺与去甲肾上腺素再摄取抑制剂(SNRIs)、类SSRIs活性的5-羟色胺(5-HT)调节剂相关内容,并更新了基于基因多态性的5-HT再摄取抑制剂类药物应用建议。本文对该指南相关内容进行解读,以期为我国5-HT再摄取抑制剂类药物个体化药物管理提供参考。

氧化应激标志物预测SSRIs治疗广泛性焦虑障碍效果的研究

目的探讨氧化应激标志物对选择性5-羟色胺再摄取抑制剂(SSRIs)治疗广泛性焦虑障碍(GAD)效果的预测价值。方法回顾性选取2022年1月至12月在湖州市第三人民医院就诊并符合美国《精神障碍诊断与统计手册-5》有关GAD诊断标准的门诊及住院患者152例,其中口服艾司西酞普兰10~20 mg/d患者75例,口服舍曲林50~200 mg/d患者77例,分别于基线期、治疗后8周末采用汉密尔顿焦虑量表(HAMA)对焦虑症状进行评定,根据SSRIs治疗8周末的HAMA评分≤7和>7分为缓解组79例和未缓解组73例。采用酶联免疫吸附试验检测患者治疗前丙二醛(MDA)、超氧化物歧化酶(SOD)、HDL、谷胱甘肽过氧化物酶(GSH-Px)、过氧化氢酶(CAT)、皮质醇、一氧化氮(NO)和脂质过氧化物(LPO)水平。比较缓解组与未缓解组血清氧化应激标志物水平的差异;分析氧化应激标志物与HAMA评分减分率的相关性;采用二元logistic回归分析影响SSRIs疗效的危险因素;采用ROC曲线分析危险因素预测SSRIs治疗缓解率的效能。结果缓解组的血清MDA、LPO水平低于未缓解组,SOD水平则高于未缓解组,差异均有统计学意义(均P<0.05)。缓解组血清MDA、LPO水平与HAMA评分减分率均呈负相关,SOD与HAMA评分减分率呈正相关(均P<0.05)。经二元logistic回归分析显示,在控制一般因素后,GAD患者血清MDA高水平和SOD低水平均是影响SSRIs治疗缓解的危险因素(均P<0.05)。ROC曲线分析显示,MDA、SOD及两者联合预测SSRIs治疗缓解率的AUC分别为0.758、0.661、0.779,MDA、SOD两者联合预测效能高于任意单一指标。结论GAD患者基线期血清MDA高水平、SOD低水平是影响SSRIs 8周末治疗缓解率的危险因素,两者联合检测有更好的预测效能。

升阳益胃汤联合SSRI类抗抑郁药治疗抑郁障碍的研究

目的观察升阳益胃汤联合5-羟色胺再摄取抑制剂(SSRI)类药物治疗抑郁障碍的疗效。方法采用随机数字表法,将2020年12月—2022年5月在河北省精神卫生中心门诊或住院治疗的120例抑郁障碍患者分为对照组和观察组,每组60例。对照组给予SSRI类药物治疗,观察组给予SSRI类药物联合升阳益胃汤治疗,2组均连续治疗8周。比较2组治疗2周、4周、8周后汉密尔顿抑郁量表17(HAMD17)评分、汉密尔顿焦虑量表(HAMA)评分、躯体化症状问卷(SSI)评分、匹兹堡睡眠质量指数量表(PSQI)评分,比较2组的疗效及药物不良反应。结果对照组53例、观察组55例完成研究。2组治疗2周、4周、8周后的HAMD17评分、HAMA评分、SSI评分均较基线时明显降低(P均<0.05),且观察组治疗2周、4周、8周后的HAMD17评分、HAMA评分、SSI评分均明显低于同期对照组(P均<0.05)。2组治疗8周后的PSQI总分和睡眠质量、睡眠时间、睡眠效率、睡眠障碍、催眠药物、日间功能评分均较基线时明显降低(P均<0.05),且观察组治疗8周后的PSQI总分和睡眠质量、睡眠时间、睡眠效率、催眠药物、日间功能评分均明显低于同期对照组(P均<0.05)。观察组治疗2周、4周、8周后治疗总有效率均明显高于同期对照组[52.7%(29/55)、74.5%(41/55)、89.1%(49/55)比39.6%(21/53)、69.8%(37/53)、81.1%(43/53),P均<0.05]。观察组不良反应发生率明显低于对照组[5.4%(3/55)比17.0%(9/53),P均<0.05]。结论升阳益胃汤联合SSRI类药物治疗抑郁障碍起效更快,对抑郁症状、焦虑症状、躯体化症状以及睡眠质量的改善幅度更大,且有一定减少不良反应作用。

5-羟色胺和去甲肾上腺素再摄取抑制剂类药物在神经病理性疼痛中的临床应用进展

5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRIs)为临床治疗神经病理性疼痛的研究热点。该文围绕SNRIs的临床应用进展作一综述,分析SNRIs的作用机制,总结SNRIs的治疗效果,讨论SNRIs在治疗中的应用挑战与限制,展望SNRIs未来研究方向与应用前景,旨在为SNRIs类药物治疗神经病理性疼痛的研究提供参考。

基于美国FAERS数据库抗抑郁药物与胎儿及新生儿的不良事件信号分析

目的基于美国食品药品监督管理局不良事件报告系统(FAERS)挖掘抗抑郁药物的使用与胎儿及新生儿不良事件的风险信号,为临床安全合理用药提供参考。方法筛选FAERS数据库2004年1月1日至2022年12月31日中怀疑抗抑郁药的不良事件报告,并通过报告比值比(ROR)法和比例报告比值比(PRR)法挖掘抗抑郁药与胎儿及新生儿之间的不良事件信号。结果共有14492例儿胎儿及新生儿异常的病例纳入研究,其中胎儿组5546例,新生儿组病例8946例。药物方面,分别有68.97%、56.35%的胎儿不良事件信号和新生儿不良事件信号为选择性5-羟色胺再摄取抑制剂(SSRI)类抗抑郁药产生。不良事件方面,51.72%胎儿不良事件信号与羊水相关,20.99%的新生儿不良事件信号与呼吸系统异常相关。对产生的不良事件信号进行二次筛选后,西酞普兰和文拉法辛信号突出,且存在说明书未载明信号。结论抗抑郁药物的整体信号特征与现有的安全性资料基本一致,但通过分组分析仍然发现了如胎儿羊水异常、新生儿心脏方面等说明书未载明不良事件,临床使用时应重点关注。

新型5-羟色胺和去甲肾上腺素重摄取抑制剂ZBH2012001通过增强单胺系统功能和抑制神经免疫炎症发挥抗抑郁作用

目的 基于调节单胺系统功能和神经免疫炎症研究新型5-羟色胺和去甲肾上腺素重摄取抑制剂(SNRI)ZBH2012001的抗抑郁作用机制。方法 (1)雄性ICR小鼠分为溶剂组(蒸馏水)、度洛西汀组(10或20 mg·kg^(-1))、ZBH2012001组(5,10和20 mg·kg^(-1)),ig给药1 h后采用小鼠悬尾实验(TST)和强迫游泳实验(FST)2个行为绝望模型评价ZBH2012001的抗抑郁作用。(2)采用放射性配体结合实验评价ZBH2012001与人源5-HT转运蛋白(hSERT)和NE转运蛋白(hNET)的靶标亲和力。(3)雄性ICR小鼠分为溶剂组(蒸馏水),度洛西汀组(10或20 mg·kg^(-1))和ZBH2012001组(5,10和20 mg·kg^(-1));ig给药1 h后采用小鼠5-羟色氨酸(5-HTP)诱导甩头实验、育亨宾毒性增强实验初步评价ZBH2012001对5-羟色胺(5-HT)和去甲肾上腺素(NE)系统功能的影响。(4)雄性ICR小鼠分为溶剂组(蒸馏水+0.1%冰醋酸),利血平模型组(蒸馏水+利血平5 mg·kg^(-1)),度洛西汀(度洛西汀20 mg·kg^(-1)+利血平5 mg·kg^(-1))组及ZBH2012001(ZBH2012001 5,10和20 mg·kg^(-1)+利血平5 mg·kg^(-1))组,ig给予ZBH2012001 1 h后ip注射利血平:通过观察眼睑下垂、体温下降和运动不能行为评价ZBH2012001对利血平诱导的单胺系统功能下调的影响;采用TST评价ZBH2012001对利血平诱导的抑郁样行为的影响;采用高效液相色谱-电化学检测法(HPLC-ECD)检测利血平单胺耗竭模型小鼠海马组织中单胺递质及其代谢产物的含量;采用ELISA检测利血平诱导单胺耗竭模型小鼠海马组织中肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)的含量;采用Western印迹法检测利血平诱导单胺耗竭模型小鼠海马组织中离子化钙结合适配分子1(Iba-1)和核因子κB(NF-κB)的表达。结果 (1)与溶剂组相比,ZBH2012001(5,10和20 mg·kg^(-1))显著减少小鼠在TST中的不动时间(P<0.01),ZBH2012001(20 mg·kg^(-1))显著减少FST中的不动时间(P<0.05)。(2) ZBH2012001可竞争抑制[^(3)H]-丙咪嗪与hSERT和[^(3)H]-尼索西汀与hNET的结合,半抑制浓度(IC_(50))值分别为84.95和712.90 nmol·L^(-1)。(3)与溶剂组相比,ZBH2012001(10和20 mg·kg^(-1))可显著增加5-HTP诱导的小鼠甩头次数(P<0.01),提高育亨宾诱导的小鼠死亡率(P<0.05,P<0.01)。(4)在利血平诱导的小鼠抑郁模型上,与溶剂组相比,利血平模型组小鼠出现眼睑下垂,体温下降和运动不能(P<0.01),悬尾不动时间显著延长(P<0.01),海马NE,5-HT和DA水平显著下降(P<0.05,P<0.01),海马5-HT代谢转换率和DA代谢转换率显著升高(P<0.01),海马TNF-α和IL-6水平显著升高(P<0.05),海马Iba-1和NF-κB表达显著升高(P<0.05);与模型组相比,ZBH2012001(5,10和20 mg·kg^(-1))可显著拮抗利血平诱导的小鼠眼睑下垂和体温下降(P<0.01),ZBH2012001(10和20 mg·kg^(-1))可显著缩短利血平小鼠的悬尾不动时间(P<0.05,P<0.01),ZBH2012001(20 mg·kg^(-1))可显著增加利血平小鼠海马NE和5-HT的水平(P<0.05),降低5-HT代谢转换率(P<0.05),显著降低利血平小鼠海马TNF-α和IL-6的水平(P<0.05),ZBH2012001(5,10和20 mg·kg^(-1))可显著降低利血平小鼠海马Iba-1表达(P<0.01),ZBH2012001(20 mg·kg^(-1))可显著降低利血平小鼠海马NF-κB表达(P<0.05)。结论 ZBH2012001通过增强单胺系统功能以及抑制神经免疫炎症发挥抗抑郁作用。

5-羟色胺选择性重摄取抑制剂联合计算机化的认知训练治疗伴有认知障碍的老年抑郁症患者的研究

目的探讨5-羟色胺选择性重摄取抑制剂(SSRI)联合计算机化的认知训练(CCT)对伴有认知障碍的老年抑郁症(LLD)患者的临床治疗效果。方法本研究为前瞻性随机对照临床研究。选取2021年5月至2022年12月于首都医科大学附属北京安定医院门诊及住院治疗的118例伴有认知障碍的LLD患者,按照随机数表法分为干预组(57例)和对照组(61例)。干预组给予临床常规SSRI类抗抑郁药治疗联合CCT干预,对照组给予临床常规SSRI类抗抑郁药治疗联合空白对照方法,两组均治疗12周。分别在治疗前及治疗后8、12周对两组患者进行阿尔茨海默病认知评估量表(ADAS-cog)、老年抑郁量表(GDS)及日常生活能力量表(ADL)评分,以评估其认知功能、精神心理状况及社会功能。结果在治疗后8周及12周时,两组的ADAS-cog、GDS量表评分均明显低于治疗前,且干预组明显低于对照组,差异均有统计学意义(P<0.05)。治疗后8周及12周时,干预组的ADL评分明显高于治疗前,且治疗后12周干预组的ADL评分明显高于对照组,差异均有统计学意义(P<0.05),而对照组治疗前后的ADL评分比较差异无统计学意义(P>0.05)。结论SSRI类抗抑郁药联合CCT治疗能够显著改善伴有认知障碍的LLD患者的认知功能和抑郁症状,可作为该类人群的有效选择。