Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ12,14PGJ2

Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ^12,14PGJ₂ a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ^12,14PGJ₂ production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ₂ and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.     

Quality of Life Impacts of Bright Light Treatment,Fluoxetine, and the Combination in Patients with Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial

Objective:Bright light therapy is increasingly recommended (alone or in combination with antidepressant medication) to treat symptoms of nonseasonal major depressive disorder (MDD). However, little is known about its impacts on quality of life (QoL), a holistic, patient-valued outcome.Methods:This study utilizes secondary outcome data from an 8-week randomized, controlled, double blind trial comparing light monotherapy (n = 32), fluoxetine monotherapy (n = 30), and the combination of these (n = 27) to placebo (n = 30). QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Treatment-related differences in QoL improvements were assessed using a repeated measures analysis of variance. The influence of potential predictors of QoL (demographic variables and change in depressive symptoms) were investigated via hierarchical linear regression.Results:Q-LES-Q-SF scores significantly improved across all treatment conditions; however, no significant differences were observed between treatment arms. QoL remained poor relative to community norms by the end of the trial period: Across conditions, 70.6% of participants had significantly impaired QoL at the 8-week assessment. Reduction in depressive scores was a significant predictor of improved QoL, with the final model accounting for 54% of variance in QoL change scores.Conclusion:The findings of this study emphasize that improvement in QoL and reduction in depressive symptoms in MDD, while related, cannot be taken to be synonymous. Adjunctive therapies may be required to address unmet QoL needs in patients with MDD receiving antidepressant or light therapies. Further research is required to explore additional predictors of QoL in order to better refine treatments for MDD.     

氟西汀在慢性丙型肝炎抗病毒治疗中的作用

超过20%的慢性丙型肝炎(CHC)患者接受IFNα抗病毒治疗后出现抑郁症,氟西汀常用于缓解此症状。氟西汀具有抗炎特性,可改变肝脏脂质合成,但其对CHC抗病毒治疗的影响及机制仍未阐明。近期研究表明氟西汀可抑制HCV感染Huh7.5细胞,且缓解了胞内活性氧生成和脂质蓄积,并通过激活STAT1和JNK通路促进IFNα介导的抗病毒作用,降低患者HCV载量及ALT水平。此外,氟西汀增强了CHC患者过氧化物酶体增殖物激活受体(PPAR)反应元件活性,其对HCV感染和脂质蓄积的抑制效应可被PPARβ/γ等拮抗物一定程度逆转,表明氟西汀可能通过调节PPARβ/γ和JNK/STAT通路抑制HCV感染、活性氧生成及脂质蓄积。     

文拉法辛与氟西汀治疗老年抑郁症对照研究

目的探讨文拉法辛与氟西汀治疗老年抑郁症的疗效及安全性。方法将60例老年抑郁症患者随机分为两组各30例,研究组口服文拉法辛治疗,对照组口服氟西汀治疗,观察8w。于治疗前及治疗1w、2w、4w、6w、8w末采用汉密顿抑郁量表评定临床疗效,副反应量表评定不良反应。结果治疗8w末,研究组总有效率93.3%,对照组为86.7%,两组总体疗效相当（χ^2=0.185,P〉0.05）。汉密顿抑郁量表评分,研究组治疗1w末起,对照组治疗2w末起较治疗前有显著下降（P〈0.05或0.01）,研究组治疗1w、2w末较对照组下降显著（P〈0.05）,其他时点评分均无显著性差异（P〉0.05）。两组不良反应均轻微。结论文拉法辛治疗老年抑郁症的疗效与氟西汀相当,且起效较氟西汀快,安全性高,依从性好。     

西酞普兰与氟西汀治疗卒中后抑郁对照研究

目的探讨西酞普兰治疗卒中后抑郁的临床疗效及安全性和对神经功能康复的影响。方法将54例卒中后抑郁患者随机分为西酞普兰组和氟西汀组各27例,观察治疗6w。于治疗前及治疗1w、2w、4w、6w末采用汉密顿抑郁量表和副反应量表评定抗抑郁疗效和不良反应,爱丁堡-斯堪的那维亚卒中量表评定神经功能缺损程度。结果治疗6w末西酞普兰与氟西汀治疗卒中后抑郁显效率分别为74.1%、70.4%;神经功能康复显效率分别为63.0%、55.6%。汉密顿抑郁量表评分西酞普兰组治疗1w末起较治疗前有极显著性下降（P〈0.01）;氟西汀组治疗2w末起有极显著性下降（P〈0.01）。爱丁堡-斯堪的那维亚卒中量表评分两组治疗6w末均较治疗前有极显著性下降（P均〈0.01）。两组不良反应均轻微,副反应量表评分无显著性差异（P〉0.05）。结论西酞普兰治疗卒中后抑郁疗效与氟西汀相当,且起效更快,安全性高,依从性好,有利于患者神经功能的康复。     

帕罗西汀与氟西汀治疗抑郁症的疗效比较

目的：评价国产帕罗西汀与氟西汀治疗抑郁症的临床效果和安全性。方法：将60例抑郁症病人随机分为两组：A组和B组．每组30例。A组采用国产帕罗西汀治疗；B组采用氟西汀治疗。两组均治疗6周。两组采用汉密尔顿抑郁量表（HAMD）评定疗效；用副反应量襄（TESS）评定副反应。结果：A组总有效率为76．7％，B组总有效率为80．0％，两组比较。差异无统计学意义（P〉0．05）；两组治疗后HAMD评分均有明显下降（P均〈0．01）。结论：国产帕罗西汀与氟西汀治疗抑郁症疗效相当，且安全。     

利培酮辅助治疗无精神病性症状抑郁症对照研究

目的探讨抗抑郁剂联合小剂量利培酮治疗无精神病性症状抑郁症的增效作用。方法将50例无精神病性症状的抑郁症患者随机分为氟西汀治疗组和氟西汀联合利培酮治疗组．治疗前及治疗第1、2、6w末采用汉密顿抑郁量表、副作用量表评定临床疗效和不良反应。结果研究组起效快．效显率高．治疗后同期汉密顿抑郁量表评分两组间比较差异均有极显著性（P〈0．01）；副作用量表评分无显著性差异（P〉0．05）。结论抗抑郁剂联合小剂量利培酮治疗无精神病性症状抑郁症具有增效作用。     

Fluoxetine Regulates Neurogenesis In Vitro Through Modulation of GSK-3β/β-Catenin Signaling

Background:

It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis.

Methods:

The aim of this study was to determine whether GSK-3β/β-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine’s regulation of GSK-3β/β-catenin signaling pathway were also examined.

Results:

Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilized β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT_1A) receptor antagonist WAY-100635.

Conclusions:

The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signaling pathway that links postsynaptic 5-HT_1A receptor activation.     

A simple assessment model to quantifying the dynamic hippocampal neurogenic process in the adult mammalian brain

Adult hippocampal neurogenesis is a highly dynamic process in which new cells are born, but only some of which survive. Of late it has become clear that these surviving newborn neurons have functional roles, most notably in certain forms of memory. Conventional methods to look at adult neurogenesis are based on the quantification of the number of newly born neurons using a simple cell counting methodology. However, this type of approach fails to capture the dynamic aspects of the neurogenic process, where neural proliferation, death and differentiation take place continuously and simultaneously. In this paper, we propose a simple mathematical approach to better understand the adult neurogenic process in the hippocampus which in turn will allow for a better analysis of this process in disease states and following drug therapies. © 2015 Wiley Periodicals, Inc.