Fluoxetine Group Research Articles

Antidepressant Activity of Nardostachys jatamansi Extract in Animal Models of Depression

Background: Depression refers to a wide range of mental health problems characterized by the loss of interest in routine activities, low mood and a range of associated emotional, cognitive, physical and behavioral symptoms. It is one of the major causes of mortality as tendency of suicidal attacks are exhibited in these patients. The diagnosis of depressive patients is very complicated in many cases and they do not respond to rational clinical prescription. In traditional medicine, Nardostachys jatamansi has been used as stimulant, antispasmodic, laxative and antiepileptic in ayurvedic and unani systems of medicine. The objective of our study was to evaluate and compare the antidepressant activity of N. jatamansi extract with fluoxetine in animal models of depression.
 Methodology: It was a preclinical experimental study in which Total 100 BALB/c mice divide into 14 groups i.e. Group 1 & 2 control 0.9% NaCl i.p for forced swimming test (FST) and tail suspension test (TST) respectively, Group 3 & 4 Fluoxetine 0.5 mg/kg i.p for FST and TST respectively, Group 5, 6 & 7 of N. jatamansi 125, 250 and 500 mg/kg respectively for FST, Group 8, 9 & 10 N. jatamansi 125, 250 and 500 mg/kg respectively for TST, Group 11 N. jatamansi (most effective dose) for Locomotor Test, Group 12 NaCl 0.9% for Yohimbine Potentiation Test (YPT), Group 13 Fluoxetine 0.5 mg/kg for YPT and Group 14 Received extract of N. jatamansi (most effective dose) for YPT. Antidepressant activity of N. jatamansi extract at different doses after induction of depression via FST and TST was recorded. Moreover the antidepressant effect was confirmed by locomotor test. YPT was also applied to comment on possible underlying mechanism.
 Results: In our study 250 mg/kg and 500 mg/kg doses of N. jatamansi showed significant reduction in immobility time when compared to controls and 500 mg/kg showed significant reduction as compared to group given fluoxetine in FST model. All the groups in TST model showed significant reduction in immobility time when compared to controls and fluoxetine given group. N. jatamansi at the dose of 500 mg/kg was found to be most effective in both the models. No significant change in locomotor activity was found in locomotor test. The percentage mortality of 50% was observed in N. jatamansi group using yohimbine potentiation test.
 Conclusion: In our study Nardostachys jatamansi showed significant reduction in immobility time when compared to controls and fluoxetine.

Randomized Clinical Trial Between Fluoxetine and Dapoxetine for Premature Ejaculation and Its Effect on Marital Relationship

INTRODUCTION: Premature ejaculation(PE) decreases sexual pleasure and quality of life, and both Fluoxetine and Dapoxetine were used in PE therapy. Dapoxetine is the first SSRI with a short half-life and fewer side effects, primarily designed for PE therapy. The aim is to evaluate and compare the effects of Fluoxetine and Dapoxetine on PE symptoms and marital satisfaction. MATERIALS AND METHODS: 44 participants aged between 18 and 64 with a PEDT score of ≥9 from Hospital USM's Primary-Care-Clinic, Kelantan Malaysia were selected and randomized into two groups: Fluoxetine(FG) and Dapoxetine Group(DG), and administered for 8 weeks with either regular Fluoxetine(20mg) or Dapoxetine (30mg) on-demand at least once a week. Premature Ejaculation Diagnostics Tool(PEDT) score was used to assess PE symptoms and Dyadic Satisfaction-Dyadic Adjustment Scale (DS-DAS) used to evaluate marital satisfaction at baseline and the 8th week. RESULT: 22 and 21 participants in FG and DG completed the study. For both groups, PEDT scores decreased substantially [from 11.41 to 5.45(P< 0.001) among FG, from 13.43 to 3.10(P<0.001) among DG]. After adjustment of the baseline PEDT score, PEDT scores in DG(6.03 vs 2.49, P><0.001) were lower at the 8th week. All groups showed significantly improved DS-DAS scores [from 34.50 to 40.68(P><0.001) in FG, from 36.57 to 44.33(P><0.001) in DG]. No marked difference in DS-DAS was scored after adjustment of the baseline DS-DAS score(41.13 vs 43.86, P=0.055) at the end of the assessment. CONCLUSION: Treatment of PE with either Fluoxetine or Dapoxetine decreases PE symptoms and increases marital satisfaction. ><0.001) among DG]. After adjustment of the baseline PEDT score, PEDT scores in DG (6.03 vs 2.49, P< 0.001) were lower at the 8th week. All groups showed significantly improved DS-DAS scores [from 34.50 to 40.68(P< 0.001) in FG, from 36.57 to 44.33(P< 0.001) in DG]. No marked difference in DS-DAS was scored after adjustment of the baseline DS-DAS score (41.13 vs 43.86, P=0.055) at the end of the assessment. CONCLUSION: Treatment of PE with either Fluoxetine or Dapoxetine decreases PE symptoms and increases marital satisfaction.

The functions of fluoxetine and identification of fluoxetine-mediated circular RNAs and messenger RNAs in cerebral ischemic stroke

ABSTRACT Fluoxetine is used to improve cognition, exercise ability, depression, and neurological functions in patients with cerebral ischemic stroke. Circular RNAs (circRNAs) play important regulatory roles in multiple diseases. However, studies regarding the fluoxetine-mediated circRNA–microRNA–messenger RNA (mRNA) axis have not been conducted. This study is aim to investigate the functions of fluoxetine and identification of fluoxetine-mediated circRNAs and mRNAs in cerebral ischemic stroke. The middle cerebral artery occlusion (MCAO) rat models were successfully established at fisrt, and then rats were intraperitoneally injected with 10-mg/kg fluoxetine hydrochloride for 14 d. Afterward, the cerebral infarction area was evaluated using triphenyltetrazolium chloride staining. High-throughput sequencing was adopted to screen the differential circRNAs and mRNAs. The candidate circRNAs, mRNAs, and potential microRNAs were verified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addtion, microRNA and circRNA binding was verified using the dual-luciferase reporter assay. Results revealed that fluoxetine markedly diminished the cerebral infarction area in rats after MCAO. The circRNAs and mRNAs were differentially expressed, which includes 879 circRNAs and 815 mRNAs between sham and MCAO groups, respectively, and 958 circRNAs and 838 mRNAs between MCAO and fluoxetine groups, respectively. In which, circMap2k1 and Pidd1 expression was significantly increased in the MCAO group but suppressed after fluoxetine treatment. Moreover, circMap2k1 directly binds with miR-135b-5p. Taken together, we verified that fluoxetine could improve brain injury after cerebral ischemic stroke. Moreover, the circMap2k1/miR-135b-5p/Pidd1 axis is potentially involved in cerebral ischemic stroke.

Dopamine receptor agonist rotigotine-loaded microspheres ameliorates sexual function deteriorated by fluoxetine in depression rats.

Low dopamine levels may cause depressive symptoms. Dopamine is also involved in sexual behavior. Rotigotine is a nonergolinic dopamine agonist. Fluoxetine, an antidepressant that acts as a selective serotonin (5-HT) reuptake inhibitor, may cause moderate or severe sexual dysfunction. This study aims to investigate the effects of rotigotine-loaded microspheres (RoMS) and rotigotine on fluoxetine-induced impairment of sexual function and their efficacy in depression-model rats. Rats with depressive-like behavior, induced by bilateral olfactory bulbectomy, were treated intragastrically with fluoxetine and co-administered RoMS or rotigotine subcutaneously. Then, copulatory behavior and open field tests were conducted. Serum luteinizing hormone and testosterone levels were assayed with enzyme-linked immunosorbent assay kits. The concentrations of 5-HT, dopamine, and norepinephrine were measured in the raphe nucleus and amygdala. The results showed that sexual function was decreased in olfactory bulbectomy rats and significantly deteriorated by fluoxetine. Co-administration of RoMS partly reversed the fluoxetine-induced impairment of sexual function, but rotigotine administration did not produce any improvement. Hyperactivity in olfactory bulbectomy rats was significantly attenuated by fluoxetine but was not influenced by co-administration of RoMS. Compared with the fluoxetine group, RoMS increased the testosterone, luteinizing hormone, dopamine, and norepinephrine levels. These findings indicated that RoMS improved the fluoxetine-induced impairment of sexual function and did not affect its antidepressant efficacy in depressive rats, which provides a potential treatment for patients with depression that can reduce the possibility of sexual dysfunction. Additionally, co-administration of fluoxetine with RoMS may be beneficial for Parkinson's disease patients with depression.

Fluoxetine Might Improve Survival of Patients With COVID-19 Pneumonia: A Retrospective Case-Control Study

Objective: We undertook this study to determine the effect of fluoxetine use on the survival of hospitalised coronavirus disease (COVID-19) pneumonia patients. Methods: This retrospective case–control chart review study used data extracted from the medical records of adults who were hospitalised with moderate or severe COVID-19 pneumonia at the Uzsoki Teaching Hospital of the Semmelweis University in Budapest, Hungary, between 17 March and 22 April 2021, and received anti-COVID-19 therapy including favipiravir, remdesivir, and baricitinib or their combination, in addition to standard medical treatment; 110 patients received 20 mg fluoxetine orally once daily as adjuvant medication. Multivariable logistic regression was used to evaluate the association between fluoxetine use and mortality.Results: Of the 269 participants, 205 (76.2%) survived and 64 (23.8%) died between days 2 and 28 after hospitalisation. Fluoxetine use was associated to a decrease of mortality risk (OR [95% CI] 0.242 [0.111–0.525], pConclusion: Provisional to confirmation in randomised controlled studies, fluoxetine may be a potent treatment for COVID-19 pneumonia.

Clinico-Biochemical Study of the Safety and Tolerability of Selective Serotonin Reuptake Inhibitors (SSRI) with Special Reference to SSRI Induced Hyponatremia in Humans and Animals

Introduction: Selective Serotonin Reuptake Inhibitors (SSRIs) are recommended as first-line anti-depressants in Major Depressive Disorder (MDD) because of their relatively benign safety profile. Hyponatremia is under reported and notorious adverse effect of SSRIs shown by few Randomised Clinical Trials (RCTs). There are only few published studies of SSRIs on serum sodium level in human and animal model. Aim: To determine SSRI induced hyponatremia in human and its correlation with age. Materials and Methods: The clinical part is a prospective cohort study whereas second part is experimental study involving animals. In clinical part-Patients of either sex, aged above 18 years, attending the Out-Patient Department (OPD) of Psychiatry of a tertiary hospital and diagnosed as MDD Diagnostic and Statistical Manual (DSM) V with the help of a senior psychiatrist, were screened and recruited in the study after satisfying the inclusion and exclusion criteria by consecutive sampling. Patients were prescribed fluoxetine (n=90), sertraline (n=55), paroxetine (n=30) and escitalopram (n=25). Parameters recorded (serum sodium) at baseline, 4th week, 8th week and 12th week. Symptoms due to hyponatremia and Adverse Drug Reactions (ADR) were also checked. Multiple group comparison at different visits for sodium level was done using one-way ANOVA and repeated measures ANOVA test and relationship of blood sodium level with age were estimated with bivariate correlation. Animal experiment was done in Pharmacology Department, animals were randomised into 5 groups control, fluoxetine, sertraline, paroxetine and escitalopram (n=6). Blood sodium checked at baseline, 2nd week and 4th week. Kruskal Wallis test and Friedman’s test done to detect changes in sodium level in follow-up period. Results: Mean age ranged between 40-50 years with equal gender distribution. Both within group and between group analysis revealed significant difference in blood sodium level (p-value< 0.0001). Hyponatremia was strongly correlated with age (correlation coefficient >-0.783). Most participants (184 out of 200) developed asymptomatic hyponatremia. Two among sertraline developed seizure leading to discontinuation to therapy. About 72 (38.09%) ADRs belonged to probable, mostly belonging to fluoxetine and sertraline group, developement of hyponatremia was 9 days (median) from starting SSRI. In animal part within group analysis revealed significant change of sodium from baseline in all drug treated animals (p-value<0.0001). Conclusion: SSRI is associated with hyponatremia and is common in elderly patients. Monitoring of serum sodium is necessary for patients on SSRI.

Fluoxetine use is associated with improved survival of patients with COVID-19 pneumonia: A retrospective case-control study.

We aimed to investigate the association between fluoxetine use and the survival of hospitalised coronavirus disease (COVID-19) pneumonia patients. This retrospective case-control study used data extracted from the medical records of adult patients hospitalised with moderate or severe COVID-19 pneumonia at the Uzsoki Teaching Hospital of the Semmelweis University in Budapest, Hungary between 17 March and 22 April 2021. As a part of standard medical treatment, patients received anti-COVID-19 therapies as favipiravir, remdesivir, baricitinib or a combination of these drugs; and 110 of them received 20 mg fluoxetine capsules once daily as an adjuvant medication. Multivariable logistic regression was used to evaluate the association between fluoxetine use and mortality. For excluding a fluoxetine-selection bias potentially influencing our results, we compared baseline prognostic markers in the two groups treated versus not treated with fluoxetine. Out of the 269 participants, 205 (76.2%) survived and 64 (23.8%) died between days 2 and 28 after hospitalisation. Greater age (OR [95% CI] 1.08 [1.05-1.11], p<0.001), radiographic severity based on chest X-ray (OR [95% CI] 2.03 [1.27-3.25], p=0.003) and higher score of shortened National Early Warning Score (sNEWS) (OR [95% CI] 1.20 [1.01-1.43], p=0.04) were associated with higher mortality. Fluoxetine use was associated with an important (70%) decrease of mortality (OR [95% CI] 0.33 [0.16-0.68], p=0.002) compared to the non-fluoxetine group. Age, gender, LDH, CRP, and D-dimer levels, sNEWS, Chest X-ray score did not show statistical difference between the fluoxetine and non-fluoxetine groups supporting the reliability of our finding. Provisional to confirmation in randomised controlled studies, fluoxetine may be a potent treatment increasing the survival for COVID-19 pneumonia.

Fluoxetine for stroke recovery improvement - the doubleblind, randomised placebo-controlled FOCUS-Poland trial.

The Fluoxetine Or Control Under Supervision (FOCUS)-Poland trial tested in a Polish cohort the hypothesis that fluoxetine improves recovery after stroke. Some studies have suggested that fluoxetine may improve functional outcomes after stroke, but these results needed confirmation. Between 2012 and 2014, large clinical trials were initiated by the FOCUS Trial Collaboration. Recently, results from the UK, Sweden, Australia, New Zealand and Vietnam have been published. We here present the results of the FOCUS trial conducted in Poland. This was a randomised, double-blind, placebo-controlled study based on the FOCUS trial protocol. Patients who had a persisting neurological deficit were randomly assigned 2-15 days after stroke onset to receive for six months either fluoxetine 20 mg/day or a placebo. The primary outcome was functional status measured using the modified Rankin Scale (mRS) at six months after randomisation. Functional status at 12 months was also assessed, as was neurological deficit at six and 12 months. Data was also collected on adverse events. Between 19 December 2014 and 13 March 2018, 30 patients were given fluoxetine and 31 were given a placebo. For the primary outcome, the distribution across mRS categories was similar for the fluoxetine and placebo groups at six months (common odds ratio 0.88; 95% confidence interval 0.31-2.50; p = 0.81), and there was no difference at 12 months (p = 0.864). There were no differences between groups in stroke recovery or in motor function recovery of the affected hand. There were no significant differences in any other secondary outcomes at six or 12 months. Patients given fluoxetine were less likely than those given the placebo to receive new antidepressant medication within six months (2 [6.67%] vs. 4 [12.90%]). Consistent with other trials based on the FOCUS protocol, fluoxetine did not improve motor recovery or general stroke outcome at six and 12 months in the Polish cohort studied. However, patients receiving fluoxetine required therapy with additional antidepressant medication less frequently.

Mechanisms Underlying the Antidepressant Effect of Acupuncture via the CaMK Signaling Pathway.

The CaMK pathway has been proven to play an important role in regulating cognitive function and emotional response. Acupuncture through the CaMK pathway improves depression-like behavior and the molecular mechanism related to its antidepressant remains to be explored. In this study, we aimed to determine whether the ability of acupuncture at Baihui (GV20) and Shenting (GV24) points to treat depression is related to the regulation of key proteins in the CaMK pathway. A rat model of depression was induced by chronic unpredicted mild stress (CUMS). Model rats in the electroacupuncture group were subjected to acupuncture at the Baihui (GV20) and Shenting (GV24) acupoints once a day for 20 min. Model rats in the fluoxetine group were gavaged with fluoxetine (1.8 mg/kg). Immunohistochemistry and Western blotting assays were used to evaluate immunoreactivity for and the protein expression levels of CaMKII, CaMKIV, and CaM. The results showed that electroacupuncture had a significant effect in rats with depression. Electroacupuncture and fluoxetine regulated the expression of key proteins in the CaMK signaling pathway, which is related to depression, in the hippocampi of rats. This indicates that acupuncture at Baihui (GV20) and Shenting (GV24) may alleviate depressive symptoms and reduce work- and life-related burdens and stress by regulating the CaMK signaling pathway.

Effects of acupuncture on Nod-like receptor protein 3 inflammasome signal pathway in the prefrontal cortex of rat with depression

To observe the influence of acupuncture on the expression of pivotal molecules of Nod-like receptor protein 3(NLRP3) inflammasome signal pathway in the prefrontal cortex of rats with depression, so as to explore the underlying mechanism of acupuncture on treatment of depression. SD rats were randomly divided into 4 groups (8 rats/group)，namely control, model, acupuncture and fluoxetine groups. The depression model was established by using chronic unpredictable mild stress for 6 weeks. During modeling, acupuncture (10 min)was applied to "Baihui"(GV20) and "Yintang"(EX-HN3) for rats of the acupuncture group once a day, with 1 day interval after consecutive 6 day-period for 36 days. Fluoxetine was given (10 mg/kg，1 mg/mL) by gavage to rats of the fluoxetine group every day during modeling for 42 days. The novelty-suppressed feeding test was used to observe feeding behavior of rats. The expressions of NLRP3 and apoptosis associated speck like protein containing a CARD (ASC), Caspase-1, and contents of IL-1β in the prefrontal cortex were detected by Western blot, immunohistoche-mistry and ELISA, separately. Compared with the control group, the latency of the novelty-suppressed feeding, and the expressions of NLRP3, ASC, Caspase-1 and IL-1β content in the prefrontal cortex of the model group were significantly increased (P<0.01). Following the interventions, the latency of the noveltysuppressed feeding，and the expressions of NLRP3, ASC, Caspase-1 and IL-1β content in the prefrontal cortex in the acupuncture and fluoxetine groups were significantly decreased (P<0.05，P<0.01). There was no significant differences in the above indicators between the acupuncture group and the fluoxetine group (P>0.05). Acupuncture could inhibit the expression of NLRP3 inflammasome signal pathway in the pre-frontal cortex, and reduce the inflammation in the brain, which may mediate the anti-depressant effect of acupuncture.

Effects of Xiaoyaosan on Depressive-Like Behaviors in Rats With Chronic Unpredictable Mild Stress Through HPA Axis Induced Astrocytic Activities.

Astrocytes in the hippocampus are immediately relevant to depressive-like behavior. By regulating their activities, Xiaoyaosan (XYS), a traditional Chinese medicine compound, works in the treatment of depression.ObjectiveChronic unpredictable mild stress (CUMS) rat model was established to observe the regulation of XYS. We investigated the behavioral changes of CUMS, the expression of corticosterone (CORT) of the hypothalamo–pituitary–adrenal (HPA) axis, the expression of Glu-NMDA receptor and astrocytes glial fibrillary acidic protein (GFAP) in the hippocampus. We also investigated whether these changes were linked to XYS.Methods80 adult SD rats were randomly divided into four groups, control group, CUMS group, XYS group, and fluoxetine group. The rats in the control group and the CUMS group received 0.5 ml of deionized water once a day by intragastrically administration. Rats in the two treatment groups received XYS (2.224g/kg/d) and fluoxetine (2.0mg/kg/d) once a day, respectively. Rat hippocampus GFAP and Glu-NMDA receptor were respectively detected by real-time fluorescent quantitative PCR and western blot. The CORT of HPA axis was detected by Elisa. Body weight, food intake, and behavioral tests, such as open field tests, the sucrose preference test, and exhaustive swimming test, were used to assess depressive-like behavior in rats.ResultsIn this work, significant behavioral changes and differences in expression of the CORT of HPA axis and hippocampal GFAP and Glu-NMDA receptor were presented in CUMS-exposed rats. Like fluoxetine, XYS improved CUMS-induced rat’s body weight, food intake, and depressive-like behavior. The study also proved that XYS could reverse the CUMS-induced changes of the CORT of HPA axis and affect the astrocytic activities and down-regulate the NR2B subunit of NMDA receptor (NR2B) level in the hippocampus.ConclusionChanges in the hippocampus GFAP and Glu-NMDA receptor may be an essential mechanism of depression. Besides, XYS may be critical to the treatment of depression by intervention the HPA axis, GFAP and Glu-NMDA receptor.

Effect of fluoxetine on the testes of adult albino rats and the possible protective role of curcumin

Fluoxetine (FLX) is extensively used for the treatment of a diversity of psychiatric disorders, mainly depression. However, it can adversely affect male fertility. This study was done to clarify the changes which take place in the testes after the oral administration of FLX and to evaluate the possible preventative role of curcumin. Seventy-six adult male albino rats were randomly divided into four equal groups. Control group: kept without any treatment. Curcumin group: received daily dose of curcumin (150mg/kg body weight) through oral gavage for 8weeks. FLX group. They were given daily dose of FLX (10mg/kg body weight) given through oral gavage for 8weeks. FLX and curcumin group. They were given FLX together with curcumin with the same previous doses through oral gavage daily for 8weeks. By the end of the experiment, blood samples were collected for the biochemical study of testosterone. All the animals were anaesthetized by ether inhalation, and the testis specimens were dissected out and weighed. The specimens were subjected to histopathological, immunohistochemical, and morphometrical evaluation. FLX decreased serum testosterone, diminished both epithelial height and diameter of seminiferous tubules, increased collagen fiber deposition in testicular tissue and induced positive immune reaction to B-cell lymphoma-2-associated X protein. In the FLX and curcumin group, the FLX-induced changes were less remarkable. Exposure to FLX led to pronounced testicular alterations. Co-administration of curcumin with FLX ameliorated these changes.

Effects of Ganmai Dazao Tang on synaptic structure of hippocampal neurons in depression model rats

Objective: To investigate the effects of Ganmai Dazao Tang on behavior and monoamine neurotransmitters in rats with depression, and to explore its potential mechanism from synaptic structure. Methods: Sixty SD rats were randomly divided into 5 groups: normal control group, model group, fluoxetine group (10.8 mg/kg), Ganmai Dazao Tang high and low dose group (9.72, 4.86 g/kg), 12 rats in each group. Except the control group, the rats in the other groups were all chronically unpredictable mild stress (CUMS) to establish a depression model, and were treated by intragastric administration for 21 days. The depression-like behaviors of rats were evaluated by sucrose consumption test and open field test. The contents of serotonin (5-HT) and norepinephrine (NE) in hippocampus were detected by ELISA. The synaptic damage of neurons was observed by Golgi staining. The synaptic structure protein expression levels of MAP-2 and GAP-43 of hippocampus were detected by Immunohistochemistry and Western blot. Results: Compared with control group, the sucrose preference and autonomic activity scores of the depression model rats were decreased significantly (P＜0.01), the levels of 5-HT and NE in hippocampus were decreased significantly (P＜0.01), and the dendritic spines were absent, and the expressions of MAP-2 and GAP-43 were down-regulated significantly (P＜0.01). After treated with Ganmai Dazao Tang, the depression-like behavior of the model rats was significantly relieved (P＜0.01), and the levels of 5-HT and NE were increased (P＜ 0.05). Dendritic spine density, length and branching were increased, the expressions of MAP-2 and GAP-43 were increased (P＜ 0.01). Conclusion: Ganmai Dazao Tang can improve the depression-like behavior of depression model rats and increase the monoamine neurotransmitter content in hippocampus, which may be related to up-regulation of synaptic structural proteins and relief of synaptic damage in neurons.

Effects of Fuhe decoction on behaviors and monoamine neurotransmitters in different brain regions of CUMS combined with social isolation depression model rats

Abstract Objective To investigate the effect of Fuhe decoction on the behavior and levels of monoamine neurotransmitters in different brain regions in a depression rat model induced by chronic unpredictable mild stimulation (CUMS) combined with social isolation. Methods Fifty male SD rats were randomly divided into a blank group, model group, fluoxetine group, Chaiqinwendan decoction group, and Fuhe decoction group. Chronic unpredictable mild stimulation combined with a social isolation method was used to replicate the depression rat model. After 42 days of administration, a tail suspension test and high-performance liquid electrochemical detection (HPLC-ECD) were used to detect the behavioral changes and changes in the content of monoamine neurotransmitters norepinephrine (NE), dopamine (DA), 5-hydroxytrytamine (5-HT), and metabolites in different brain regions of rats in each group before and after treatment. Results Compared with the model group, the epinephrine (E) content in the Fuhe decoction group was highly significantly increased (P Conclusion Fuhe decoction can improve the depression-like behaviors of model rats, and its antidepressant effect may be related to the increase in 5-HT content in the prefrontal cortex and hippocampus of rats.

Xiaoyaosan improves depressive-like behaviors by regulating the NLRP3 signaling pathway in the rat cerebral cortex

Abstract Objective To observe changes in the molecular expression of the NLR Family Pyrin Domain Containing Protein 3 (NLRP3) pathway in depressed rats after treatment with Xiaoyaosan, and identify the regulatory mechanism of this compound. Methods Male Sprague–Dawley rats were randomly divided into five groups with 12 rats in each group, including the control group, model group, Fluoxetine group, Xiaoyaosan group, and MCC950 group. A depression model was generated by chronic immobilization stress (induced by 3 h of restraint immobilization every day), and the drugs were administered at the same time in each group for 21 days. The effects of Xiaoyaosan on behavioral changes of depressed rats were observed through macroscopic characterization, body mass, open field experiments, and a sucrose preference test. The mRNA and protein expression of the NLRP3 signaling pathway was examined by fluorescence real-time quantitative PCR and Western blot assays. Results The Xiaoyaosan group, Fluoxetine group, and MCC950 group rats showed improved depressive behavior and an increased weight of sucrose water consumption. The protein and mRNA expression levels of NLRP3, Caspase-1, and IL-1β were also decreased in the Fluoxetine, Xiaoyaosan, and MCC950 groups. Conclusion NLRP3, Caspase-1, and IL-1β protein and mRNA expression levels were increased in the cortex of depressed rats, while Xiaoyaosan protected cortical tissue in these rats by decreasing NLRP3, Caspase-1, and IL-1β protein and mRNA expression.

Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial.

Studies have suggested that fluoxetine could improve neurological recovery after stroke. The Efficacy oF Fluoxetine-a randomisEd Controlled Trial in Stroke (EFFECTS) trial aimed to assess whether administration of oral fluoxetine for 6 months after acute stroke improves functional outcome. EFFECTS was an investigator-led, multicentre, randomised, placebo-controlled, double-blind, parallel group trial that enrolled patients aged 18 years or older between 2 and 15 days after stroke onset in 35 stroke and rehabilitation centres in Sweden. Eligible patients had a clinical diagnosis of ischaemic or intracerebral haemorrhage, brain imaging that was consistent with intracerebral haemorrhage or ischaemic stroke, and had at least one persisting focal neurological deficit. A web-based randomisation system that incorporated a minimisation algorithm was used to randomly assign (1:1) participants to receive oral fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Patients, care providers, investigators, and outcomes assessors were masked to the allocation. The primary outcome was functional status, measured with the modified Rankin Scale (mRS) at 6 months, analysed in all patients with available mRS data at the 6-month follow-up; we did an ordinal analysis adjusted for the minimisation variables used in the randomisation. This trial is registered with EudraCT, 2011-006130-16; ISRCTN, 13020412; and ClinicalTrials.gov, NCT02683213. Between Oct 20, 2014, and June 28, 2019, 1500 patients were enrolled, of whom 750 were randomly assigned to fluoxetine and 750 were randomly assigned to placebo. At 6 months, mRS data were available for 737 (98%) patients in the fluoxetine group and 742 (99%) patients in the placebo group. There was no effect of fluoxetine on the primary outcome-distribution across mRS score categories-compared with placebo (adjusted common odds ratio 0·94 [95% CI 0·78 to 1·13]; p=0·42). The proportion of patients with a new diagnosis of depression was lower with fluoxetine than with placebo (54 [7%] patients vs 81 [11%] patients; difference -3·60% [-6·49 to -0·71]; p=0·015), but fluoxetine was associated with more bone fractures (28 [4%] vs 11 [2%]; difference 2·27% [0·66 to 3·87]; p=0·0058) and hyponatraemia (11 [1%] vs one [<1%]; difference 1·33% [0·43 to 2·23]; p=0·0038) at 6 months. Functional outcome after acute stroke did not improve with oral fluoxetine 20 mg once daily for 6 months. Fluoxetine reduced the occurrence of depression but increased the risk of bone fractures and hyponatraemia. Our results do not support the use of fluoxetine after acute stroke. The Swedish Research Council, the Swedish Heart-Lung Foundation, the Swedish Brain Foundation, the Swedish Society of Medicine, King Gustav V and Queen Victoria's Foundation of Freemasons, and the Swedish Stroke Association (STROKE-Riksförbundet).

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial.

Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2-15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76-1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke. National Health and Medical Research Council of Australia.

Effect of Xiaoyaosan on Colon Morphology and Intestinal Permeability in Rats With Chronic Unpredictable Mild Stress.

PurposeIn our present study, a rat depression model induced by 6 weeks of chronic unpredictable mild stress (CUMS) was established, and we investigated how Xiaoyaosan affects the intestinal permeability of depressed rats and alterations in tight-junction proteins (TJs) involved in this process.MethodsThe rat depression model was established using CUMS for 6 consecutive weeks. A total of 40 healthy male Sprague-Dawley rats were randomly sorted into four groups: the control group, CUMS group, Xiaoyaosan group, and fluoxetine group. All groups, excluding the control group, were subjected to the 6-week CUMS program to generate the depression model. Body weight, food intake, and behaviors were observed during the modeling period. Histopathological alterations of colon tissue were evaluated by hematoxylin-eosin staining (H&E), and mucus-containing goblet cells were detected by periodic acid-Schiff (PAS) staining. The ultrastructural morphology of colonic mucosa was observed by transmission electron microscopy. Furthermore, immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to determine the expression of TJs. The concentrations of 5-hydroxytryptamine (5-HT) in the hypothalamus and colon were also assessed using enzyme-linked immunosorbent assay (ELISA).ResultsTreatment of depressed rats with Xiaoyaosan alleviated depression-like behaviors as demonstrated by increases in the total distance traveled, the number of entries into the central area in the open field test, the duration spent in the central area, and sucrose preference. Xiaoyaosan treatment also increased body weight gain and food intake in depressed rats. Moreover, Xiaoyaosan treatment effectively improved the colonic pathological and ultrastructural changes, upregulated the expression of ZO-1, occludin, and claudin-1 in the colon, and increased 5-HT levels in the hypothalamus and colonic mucosa.ConclusionsXiaoyaosan treatment attenuates depression-like behaviors caused by CUMS and ameliorates CUMS-induced abnormal intestinal permeability, which may be associated with the expression of TJs. These results suggest that Xiaoyaosan exerts an antidepressant effect that may be related to an improvement of intestinal barrier function via the brain-gut axis.

Effects of modified Xiaoyao San on TLR4/NF-κB pathway in hippocampal microglia of LPS-induced depression model rats

To investigate the effects of modified Xiaoyao San on TLR4/NF-κB pathway in hippocampal microglia of LPS-induced depression model rats, and to explore its antidepressant mechanism. SD rats were randomly divided into control, model, fluoxetine (10 mg·kg-1), low and high dose of modified Xiaoyao San (3.64, 7.28g·kg-1) group. The depression model was established by chronic LPS injection (ip, 0.5 mg·kg-1) and rats were treated by intragastric administration for 14 days. After the model was established, the depression-like behavior of rats was evaluated by open field and forced swimming test. The expression of microglia marker protein Iba-1 was detected by immunohistochemistry. The levels of TNF-α and IL-6 in hippocampal homogenate were detected by ELISA method and the expressions of TLR4 and NF-κB protein in hippocampus were detected by Western blot. Compared with control group, the depression-like behavior was significant in model group rats (P＜0.01), the microglia in the brain was activated (P＜0.01), the contents of TNF-α and IL-6 in the hippocampus were increased (P＜0.01), and the expression levels of TLR4 and NF-κB proteins were up-regulated (P＜0.01). Compared with model group, the depression-like behavior of the rats in the fluoxetine and high-dose modified Xiaoyao San group was significantly alleviated (P＜0.05), the expression of Iba-1 in microglia returned to normal (P＜0.01), the contents of TNF-α and IL-6 were decreased (P＜0.01), and the expression levels of TLR4 and NF-κB protein were decreased (P＜0.05). Compared with fluoxetine group, the high-dose modified Xiaoyao San group had no statistically significant difference in each index, suggesting that there was no significant difference in the antidepressant effect between the two groups. Modified Xiaoyao San can significantly improve the depression-like behavior in rats, and its mechanism may be related to inhibiting the TLR4/NF-κB pathway of microglia and down-regulating the expression of inflammatory factors.

Antidepressant-Like Effects of Chaihu Shugan Powder () on Rats Exposed to Chronic Unpredictable Mild Stress through Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis.

To investigate the antidepressant-like effects of Chaihu Shugan Powder (CSP, ) and to explore its underlying mechanisms. Thirty-two Sprague-Dawley rats were randomly divided into control (CON), chronic unpredictable mild stress (CUMS), fluoxetine (FLU), and CSP groups, 8 rats in each group. All of the rats except for those in the control group were subjected to 3 consecutive weeks of CUMS to establish the depression model. The open field test (OFT), forced swimming test (FST), and sucrose preference test were used to assess the anti-anxiety and antidepressant effects of CSP. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling was used to determine the apoptosis rate in the hippocampal tissues. The mRNA and protein levels of glucose-regulated protein (GRP) 78, spliced X-box-binding protein (XBP)-1, CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, and c-Jun N-terminal kinase (JNK) in the hippocampus of rats were evaluated by real-time PCR and Western blot analysis, respectively. Administration of CSP alleviated anxiety and depression-like behavior in CUMS rats, as revealed by enhanced time and distance in the center of the OFT (P<0.05), an increased preference for sucrose, and longer swimming time and shorter immobility time during the FST (all P<0.05). In addition, CSP treatment significantly reduced the rate of apoptosis in rat hippocampal neurons (P<0.05). The mRNA and protein expression levels of GRP78, spliced XBP-1, and CHOP were down-regulated along with the expression of caspase-12 and cleaved caspase-12 proteins (all P<0.05), whereas total and phosphorylated JNK1 protein levels did not differ significantly between control and CSP-treated rats. CSP can improve depression-like behavior in rats exposed to CUMS, possibly by suppressing CHOP and caspase-12 mediated apoptosis in the rat hippocampus.