Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression

Depressed individuals who carry the short allele for the serotonin-transporter-linked promotor region of the gene are more vulnerable to stress and have reduced response to first-line antidepressants such as selective serotonin reuptake inhibitors. Since depression severity has been reported to correlate with brain iron levels, the present study aimed to characterise the potential antidepressant properties of the iron chelator deferiprone. Using the serotonin transporter knock-out (5-HTT KO) mouse model, we assessed the behavioural effects of acute deferiprone on the Porsolt swim test (PST) and novelty-suppressed feeding test (NSFT). Brain and blood iron levels were also measured following acute deferiprone. To determine the relevant brain regions activated by deferiprone, we then measured c-Fos expression and applied network-based analyses. We found that deferiprone reduced immobility time in the PST in 5-HTT KO mice and reduced latency to feed in the NSFT in both genotypes, suggesting potential antidepressant-like effects. There was no effect on brain or blood iron levels following deferiprone treatment, potentially indicating an acute iron-independent mechanism. Deferiprone reversed the increase in c-Fos expression induced by swim stress in 5-HTT KO mice in the lateral amygdala. Functional network analyses suggest that hub regions of activity in mice treated with deferiprone include the caudate putamen and prefrontal cortex. The PST-induced increase in network modularity in wild-type mice was not observed in 5-HTT KO mice. Altogether, our data show that the antidepressant-like effects of deferiprone could be acting via an iron-independent mechanism and that these therapeutic effects are underpinned by changes in neuronal activity in the lateral amygdala. Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01257-0.     

Protective effects of peony glycosides against corticosterone-induced cell death in PC12 cells through antioxidant action

Aim of the study

Previous studies in our laboratory have shown that total glycosides of peony (TGP) produced antidepressant-like action in various mouse models of behavioral despair. However, the molecular mechanism by which TGP exerts antidepressant-like effect is not fully understood. This study examined the protective ffects of TGP against corticosterone-induced neurotoxicity in rat pheochromocytoma (PC12) cells and ts possible mechanisms.

Materials and methods

The direct antioxidant effect of TGP was investigated by using a 2,2′-azinobis-(3-ethylbenzothiazoline- 6-sulphonic acid) (ABTS) radical cation-scavenging assay in a cell-free system. PC12 cells were treated with 200 μM of corticosterone in the absence or presence of TGP in varying concentrations for 48 h. Cell viability, lactate dehydrogenase (LDH) activity, intracellular reactive oxygen species (ROS) level, malondialdehyde (MDA) content, glutathione (GSH) content, superoxide dismutase (SOD) activity, and catalase (CAT) activity were then determined.

Results

TGP displayed antioxidant properties in the cell-free system, and the IC50 value in the ABTS radical cation-scavenging assay was 9.9 mg/L. TGP treatment at increasing doses (1-10 mg/L) protected against corticosterone-induced cytotoxicity in PC12 cells in a dose-dependent manner. The cytoprotection afforded by TGP treatment was associated with decreases in the intracellular ROS and MDA levels, and increases in the GSH level, SOD activity, and CAT activity in corticosterone-treated PC12 cells.

Conclusion

The results suggest that TGP has a neuroprotective effect on corticosterone-induced neurotoxicity in PC12 cells, which may be related to its antioxidant action.     

我院2005～2007年抗抑郁药利用分析

目的：评价我院门诊患者抗抑郁药的应用现状及趋势，为临床合理用药提供参考。方法：对我院2005～2007年门诊患者使用抗抑郁药的种类、销售金额、用药频度（DDDs）等进行统计、分析。结果：抗抑郁药的处方数、购药金额及DDDs等逐年增长，5-羟色胺再摄取抑制剂（SSRI）是临床治疗抑郁症的首选药物，3年处方数比例都在80％以上。帕罗西汀、西酞普兰、氟西汀、舍曲林等SSRI在3年中都是应用最多的药物。结论：本院的抗抑郁药应用基本合理。SSRI类抗抑郁药的应用3年中占主导地位．三环类抗抑郁药（TCAs）应用较少。     

抑郁障碍患者楔前叶功能连接与抗抑郁药物早期疗效的相关性

背景 默认网络内楔前叶功能活动与抗抑郁药物的疗效有关。然而,楔前叶功能网络与抗抑郁药物早期疗效的关系仍不清楚。 目的 探索抑郁障碍患者楔前叶功能连接（FC）与抗抑郁药物早期疗效的关系,以期寻找预测抗抑郁药物早期疗效的神经生物标志物。 方法 连续纳入2017年7月—2019年2月在四川大学华西医院心理卫生中心就诊的、符合《精神障碍诊断与统计手册（第5版）》（DSM-5）诊断标准的47例抑郁障碍患者。采集患者基线期静息态功能磁共振（rs-fMRI）数据及临床信息。患者接受2周抗抑郁药物治疗,根据治疗2周时16项抑郁症状快速自评量表（QIDS-SR16）评分减分率是否≥20%,将患者分为早期改善组（ n=27）和未改善组（ n=20）。以双侧楔前叶为种子点,计算楔前叶与全脑FC值,比较两组基线期楔前叶FC的差异。采用Pearson相关分析考查差异有统计学意义的脑区的FC值与QIDS-SR16评分及其减分率之间的相关性。 结果 早期改善组左侧楔前叶与左侧中央前回的FC值、右侧楔前叶与右侧梭状回的FC值均高于未改善组（GRF校正, P<0.01）。抑郁障碍患者左侧楔前叶与左侧中央前回的FC值、右侧楔前叶与右侧梭状回的FC值与QIDS-SR16总评分减分率均呈正相关（ r=0.475、0.297, P均<0.05）。 结论 基线期较低的左侧楔前叶与左侧中央前回、右侧楔前叶与右侧梭状回的FC与较差的抗抑郁药物早期疗效有关,楔前叶FC可能是预测抗抑郁药物早期疗效的潜在指标。     

抗精神类药物在化疗致呕吐不良反应的临床处理方法

目的:探讨抗精神类药物用于化疗致呕吐不良反应中的应用方法及效果。方法:选择化疗致呕吐患者60例,依照床位单双号随机、平均分为研究组与对照组,对照组予以常规止吐处理,研究组在常规止吐基础上联合抗精神类药物奥氮平止吐,对比两组患者止吐效果和生活质量。结果:研究组患者治疗有效率为36.7%、无效率为63.3%,有效率明显高于对照组(P=0.013);研究组患者食欲、睡眠、生活、精神状态、沟通交往、生活乐趣改善率分别为56.7%、36.7%、43.3%、43.3%、26.7%、26.7%,改善率均高于对照组(P<0.05)。结论:抗精神类药物用于化疗致呕吐不良反应治疗中有确切的止吐效果,且能对患者食欲、睡眠、精神状态等起到调节作用,在止吐的同时改善生活质量。     

The change of insulin levels after six weeks antidepressant use in drug-naïve major depressive patients

Background

A reciprocal relationship between diabetes risk and depression has been reported. There are few studies investigating glucose–insulin homeostasis before and after short-term antidepressant treatment in drug-naïve major depressive disorder (MDD) patients.

Methods

This study included 104 healthy controls and 50 drug-naïve MDD patients diagnosed according to the DSM-IV criteria. These MDD patients were randomly assigned to receive fluoxetine or venlafaxine for six weeks. Depressive symptoms, body mass index, fasting plasma levels of glucose and insulin were measured.

Results

Compared to the healthy controls, the fasting plasma insulin and the homeostasis model of assessment for pancreatic β-cell secretory function (HOMA-β) was significantly lower in the MDD patients before antidepressant treatment (7.7±4.8 μIU/mL vs. 5.1±4.2 μIU/mL, p=0.006; 114.2±72.3% vs. 74.8±52.0%, p=0.005, respectively). However, these indices were not correlated with depression severity. After 6 weeks of fluoxetine or venlafaxine treatment, the level of HOMA-β borderline significantly increased (108.1±75.5%, p=0.059).

Limitations

The study was limited by the follow-up duration and lack of a placebo group.

Conclusions

Antidepressants might affect insulin secretion independently of the therapeutic effects on MDD. Further studies are needed to investigate the long-term effects of antidepressants on insulin regulation in MDD patients.     

The utilization of psychopharmacological treatment and medication adherence among Medicaid enrolled children and adolescents with bipolar depression

Background

To examine the psychotropic medication utilization and compare adherence to treatment regimens in pediatric bipolar depression patients.

Methods

2003–2007 MAX data from four geographically diverse states were used. According to the regimen received by the patients (6–18 years) in the first month after the index bipolar depression diagnosis, patients were categorized into six mutually exclusive groups. The month to month change of treatment regimen in each group was then assessed during the 6 month post-index bipolar depression diagnosis. Adherence to each regimen was measured as continuation of the initial regimen, switch to a new regimen, augmentation with medication from a different therapeutic category, and discontinuation of all pharmacotherapies. Repeated measure analysis was conducted to compare the trend of each adherence measure across the study groups.

Results

Of the 5,460 subjects identified, 15.39% received antipsychotic monotherapy, 9.43% received mood stabilizer monotherapy, 5.77% received antidepressant monotherapy, 26.48% received mood stabilizer–antipsychotic polytherapy, 22.51% received antidepressant polytherapy, and 19.89% received antipsychotic–mood stabilizer–antidepressant polytherapy. At the end of the follow-up period, over 50% of the 1st month polytherapy users and less than 50% of the monotherapy users were continuing their initial regimen. Repeated measure analysis using antipsychotic monotherapy as the reference group suggested differences in trend slopes (p<0.05).

Limitations

In absence of structured clinical evaluation, bipolar disorder diagnoses cannot be ascertained in this study.

Conclusions

Bipolar depression patients were predominantly treated with combinations of psychotropic drugs. Potentially questionable practice, such as antidepressant monotherapy was used only in a small fraction of patients. Combination regimens had better adherence as compared to monotherapies.     

Kétamine,psilocybine, et antidépresseurs d'action rapide : de nouvelles promesses pour la psychiatrie?

The hypothesis of monoaminergic deficiency has long dominated the conceptual framework for the development of new antidepressant strategies, but the limits of conventional antidepressant treatments targeting monoaminergic signaling have motivated the search for new antidepressant pathways. The success of ketamine in the management of depressive disorders has provoked a renewed interest in hallucinogenic substances such as psilocybin targeting the serotonergic signaling 5HT^2A and neurosteroid allosteric modulator of γ-aminobutyric acid (GABAA) receptors such as brexanolone. Unlike conventional treatments, these modulators of glutamatergic, serotonergic and GABAergic systems exert a rapid antidepressant effect ranging from 24 hours to a week. Apart from their clinical interest and the fantasized search for a “miracle” molecule that jointly meets the expectations of patients and clinicians, these new targets could lead to the identification of potential new biomarkers for the development of rapid-acting antidepressants and redefine therapeutic strategies in mood disorders.