Search

Background: To date, the clinical equivalence between branded and generic medications remains debate and may sometimes be a reason why psychiatrists are hesitant to prescribe generic medications. Depression is recognized to exacerbate suicide risk globally and selective serotonin reuptake inhibitors, such as fluoxetine are common treatment options. Therefore, this study aimed to explores differences in suicidal risks between users of branded and generic fluoxetine in Taiwan., Methods: This cohort study used Taiwan Longitudinal Health Insurance Database, encompassing 2 million individuals covered by National Health Insurance (NHI) program. The full cohort consisted of 32,298 fluoxetine new users. Then, 7,380 branded and 7,380 propensity score matched (PSM) generic fluoxetine new users were identified. The study further utilized Cox proportional hazards models to assess risk of 5-year suicidal ideation, suicide mortality, and all-cause mortality., Results: The study revealed that the adjusted hazard ratios (HRs) for suicidal ideation, suicide mortality and all-cause mortality in branded users were 0.766 (95% CI, 0.497 - 1.181), 0.660 (95% CI, 0.447 - 0.975), and 0.942 (95% CI, 0.849 - 1.045), respectively, when compared with matched generic fluoxetine users. Stratified and sensitivity analyses showed the lower risk of suicide mortality in specific subgroups, such as male (adjusted HRs = 0.536, 95% CI = 0.306-0.939) and young branded users (adjusted HRs = 0.549, 95% CI = 0.334-0.904)., Conclusion: This study observed trends in the prevention effects of suicide-related risks. However, only suicide mortality was statistically significant, especially in males and those aged < 40 years. These insights may assist clinicians and policymakers in decision-making., Clinical Trial Number: NA (This study is a cohort study utilizing the national health insurance database, not a clinical trial)., Competing Interests: Declarations. Ethics approval and consent to participate: The Institutional Review Board of Tri-Service General Hospital, Taiwan, approved this study (C202205001). Consent for publication: Not applicable. Competing interests: No financial relationships with any organizations that could have an interest in the submitted work in the past three years. Additionally, no other relationships or activities could appear to have influenced the submitted work. Li-Ting Kao reports receiving research funding from IQVIA outside the submitted work. No other disclosures were reported., (© 2024. The Author(s).)

Background: We explored if the administration of fluoxetine, recognized for its potential in adipocyte browning, entails a differential risk of coronary heart disease (CHD) in comparison to other SSRI medications., Methods: Using the National Health Insurance Research Database of Taiwan from 2000 to 2013, we conducted a retrospective cohort study. The exposure cohort comprised individuals prescribed fluoxetine for over 90 days (n = 2,228). Conversely, those administered other SSRIs (excluding fluoxetine) for a duration surpassing 90 days were designated as the non-exposed cohort (n = 8,912). CHD incidence served as our primary outcome measure, and we employed Cox proportional hazards models to scrutinize the relationship between fluoxetine exposure and CHD development rates., Results: Compared with the non-exposed cohort, the fluoxetine use had a significantly decreased 21% risk of developing CHD in the exposed cohort (adjusted hazard ratio: 0.79%, 95% confidence interval: 0.68-0.92). Noticeably, results indicated that there was an inverse association between the fluoxetine exposure and the risk of CHD, regardless of whether men, women or other age groups., Conclusion: Our findings suggest that clinical use of fluoxetine was associated with a 21% reduced risk of CHD relative to other SSRI prescriptions., (© 2024. The Author(s).)

Training and maintaining a service dog requires extensive time and financial resources. The emotional bond between service dogs and their handlers poses unique challenges when dogs develop behavioral issues. We present a case of an otherwise healthy adult service dog exhibiting acute environmental fears, hindering her job performance. The dog's fear responses escalated in various settings, including school and home environments. Diagnostic evaluation ruled out medical pathology, leading to a diagnosis of nonsocial environmental fear and generalized anxiety. A multimodal treatment approach involving environmental management, antidepressant medication (fluoxetine), and behavior modification was implemented. Desensitization and counterconditioning protocols targeted specific triggers, such as shiny floors and elevators. Eight weeks after treatment initiation, the dog showed improvement, enabling a modified behavior treatment plan to be implemented as she gradually returned to work with reduced fear responses. Follow-up revealed sustained progress with additional dosage adjustment of fluoxetine., (© 2024 by American Animal Hospital Association.)

Purpose: To evaluate the effects of oral fluoxetine on visual acuity and visual-evoked potential (VEP) parameters in adults patching for amblyopia., Methods: In this randomized clinical trial, adults (>18 years of age) with anisometropic or strabismic amblyopia were assigned randomly to a treatment (fluoxetine) group or a placebo group. Standard treatments for amblyopia (glasses prescription and patching) were prescribed for 4 months for all patients beforehand. The first group received fluoxetine (20 mg per day) and the second group received a placebo for 3 months, both continuing patching. Visual acuity evaluation and VEP were performed before and after treatment., Results: A total of 55 participants were included: 29 in the fluoxetine group and 26 in the placebo group. Mean age was 27.2 ± 8.6 years (18-54). The mean logMAR visual acuity of the amblyopic eye improved by 0.20 ± 0.24 (0-0.8) in the fluoxetine group (P < 0.001) and by 0.08 ± 0.15 (0-0.7) in the placebo group (P = 0.01); mean logMAR improvement was significantly higher in the fluoxetine group than in the placebo group (P = 0.04). At the end of the study, mean visual acuity of the fluoxetine group (0.36 ± 0.21 log MAR) was better than the placebo group (0.43 ± 0.35 log MAR). Among the VEP parameters, N75 amplitude did not change significantly in either group relative to baseline, but the changes were statistically significantly different between the two groups (P = 0.05); N135 latency improved from baseline in the fluoxetine group (P = 0.03)., Conclusions: In our study cohort, fluoxetine treatment resulted in greater improvement in visual acuity than placebo during patching for adult amblyopia., (Copyright © 2024 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

β-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of β-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and β-arrestin2 -/- mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the β-arrestin2 -/- CMS group, these results of the β-arrestin2 -/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out β-arrestin2. Mass spectrometry implying that FLX promoted the binding of β-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT 2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to β-arrestin2. We further found that the lack of β-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, β-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT 2B R-β-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Three large randomized controlled trials of fluoxetine for stroke recovery have been performed. We performed an individual patient data meta-analysis (IPDM) on the combined data., Methods: Fixed effects meta-analyses were performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined., Findings: The three trials recruited a combined total of 5907 people (mean age 69.5 years (SD 12.3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, United Kingdom, Sweden, and Vietnam; and randomized them to fluoxetine 20 mg daily or matching placebo for 6 months. Data on 5833 (98.75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0.96, 95% CI 0.87 to 1.05, p = 0.37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit, or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2.64% vs 1.8%, p = 0.03), falls with injury (6.26% vs 4.51%, p = 0.03), fractures (3.15% vs 1.39%, p < 0.0001) and hyponatremia (1.22% vs 0.61%, p = 0.01) but reduced new depression (10.05% vs 13.42%, p < 0.0001). At 12 months, there was no difference in adjusted mRS (n = 5760; common OR 0.98, 95% CI 0.89 to 1.07). Sensitivity analyses gave the same results., Interpretation: Fluoxetine 20 mg daily for 6 months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Posttraumatic stress disorder (PTSD) is a complex mental disorder notable for traumatic experience memory. Although current first-line treatments are linked with clinically important symptom reduction, a large proportion of patients retained to experience considerable residual symptoms, indicating pathogenic mechanism should be illustrated further. Recent studies reported that newly formed myelin could shape neural circuit function and be implicated in fear memory preservation. However, its role in PTSD remains to be elucidated. In this study, we adopted a restraint stress-induced PTSD mouse model and found that PTSD-related neuropsychiatric symptoms were accompanied by increased myelination in the posterior parietal cortex and hippocampus. Fluoxetine, but not risperidone or sertraline, has a more profound rescue effect on neuropsychological behaviors and myelin abnormalities. Further mechanistic experiments revealed that fluoxetine could directly interfere with oligodendroglial differentiation by upregulating Wnt signaling. Our data demonstrated the correlation between PTSD and abnormal myelination, suggesting that the oligodendroglial lineage could be a target for PTSD treatment., (© 2024. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Sutton has received research grants from Boehringer-Ingelheim, Gilead Sciences, Alexion Pharmaceuticals, and United Therapeutics, all for projects unrelated to study. J.A. is a co-founder of DiceRx, iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and, unrelated to this work, he has been a board member for Theragen and consultant for Abbvie/Allergan, Boehringer-Ingelheim, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences. The other authors declare no competing interests.

Chlorpyrifos (CPF) is a widely used organophosphate insecticide in agriculture and homes. Exposure to organophosphates is associated with neurotoxicity. Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) that is widely prescribed for depression and anxiety disorders. Studies have shown that FLX has neuroprotective, anti-inflammatory, antioxidant, and antiapoptotic effects. The molecular mechanisms underlying FLX are not fully understood. This work aimed to investigate the potential neuroprotective effect of FLX on CPF-induced neurotoxicity and the underlying molecular mechanisms involved. Thirty-two rats were randomly divided into four groups: (I) the vehicle control group; (II) the FLX-treated group (10 mg/kg/day for 28 days, p.o); (III) the CPF-treated group (10 mg/kg for 28 days); and (IV) the FLX+CPF group. FLX attenuated CPF-induced neuronal injury, as evidenced by a significant decrease in Aβ and p-Tau levels and attenuation of cerebral and hippocampal histological abrasion injury induced by CPF. FLX ameliorated neuronal oxidative stress, effectively reduced MDA production, and restored SOD and GSH levels through the coactivation of the PPARγ and SIRT1 proteins. FLX counteracted the neuronal inflammation induced by CPF by decreasing MPO, NO, TNF-α, IL-1β, and IL-6 levels by suppressing NF-κB and JAK1/STAT3 activation. The antioxidant and anti-inflammatory properties of FLX help to prevent CPF-induced neuronal intoxication., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 ( DLX5/6 ) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5 , Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients' response to antidepressant treatment.

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments., Competing Interests: Declaration of competing interest Meaning all authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Fluoxetine, a commonly prescribed medication for depression, has been studied in Alzheimer's disease (AD) patients for its effectiveness on cognitive symptoms. The aim of this systematic review is to investigate the therapeutic potential of fluoxetine in cognitive decline in AD, focusing on its anti-degenerative mechanisms of action and clinical implications. According to PRISMA, we searched MEDLINE, up to 1 April 2024, for animal and human studies examining the efficacy of fluoxetine with regard to the recovery of cognitive function in AD. Methodological quality was evaluated using the ARRIVE tool for animal AD studies and the Cochrane tool for clinical trials. In total, 22 studies were analyzed (19 animal AD studies and 3 clinical studies). Fluoxetine promoted neurogenesis and enhanced synaptic plasticity in preclinical models of AD, through a decrease in Aβ pathology and increase in BDNF, by activating diverse pathways (such as the DAF-16-mediated, TGF-beta1, ILK-AKT-GSK3beta, and CREB/p-CREB/BDNF). In addition, fluoxetine has anti-inflammatory properties/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome. Only three clinical studies showed that fluoxetine ameliorated the cognitive performance of people with AD; however, several methodological issues limited the generalizability of these results. Overall, the high-quality preclinical evidence suggests that fluoxetine may have neuroprotective, antioxidant, and anti-inflammatory effects in AD animal models. While more high-quality clinical research is needed to fully understand the mechanisms underlying these effects, fluoxetine is a promising potential treatment for AD patients. If future clinical trials confirm its anti-degenerative and neuroprotective effects, fluoxetine could offer a new therapeutic approach for slowing down the progression of AD.

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), were studied for their potential application in different diseases, especially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from the SSRIs class for the treatment of several neuropsychiatric disorders with a favorable safety profile. FLX exhibited different oncolytic effects via mechanisms distinct from its main serotonergic activity. Taking advantage of its ability to rapidly penetrate the blood-brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of the literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers, highlighting the multifaceted activities of FLX and its ability to interrupt cancer proliferation via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX onto carriers to enhance its safety and efficacy on cancer cells. This is the first review article extensively summarizing all previous FLX repurposing studies for the management of cancer.

Objective: Major depressive disorder (MDD) presents a significant psychosocial burden, and there is an unmet need for additional treatment options in pediatric patients. Here, we report the results of two phase 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group studies evaluating the efficacy and safety of levomilnacipran extended release in children and adolescents with MDD. Methods: In the first study, LVM-MD-11, patients aged 12-17 years received daily doses of levomilnacipran 40 mg ( n  = 134), levomilnacipran 80 mg ( n  = 138), fluoxetine 20 mg ( n  = 134), or placebo ( n  = 141). In the second study, LVM-MD-14, patients aged 7-17 years received levomilnacipran 40 to 80 mg ( n  = 166), fluoxetine 20 mg ( n  = 166), or placebo ( n  = 160) daily. Primary and secondary efficacy endpoints were changes in Children's Depression Rating Scale-Revised (CDRS-R) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively. Results: In LVM-MD-11, there were no significant differences in change in CDRS-R total score between patients treated daily with placebo (least squares mean [LSM] change in CDRS-R total score -22.9) versus levomilnacipran 40 mg (-23.3; p  = 0.8035) or 80 mg (-22.6; p  = 0.8681). Similarly, in LVM-MD-14, there were no significant differences in LSM change in CDRS-R total score with placebo (-21.3) versus levomilnacipran 40 to 80 mg daily (-23.0; p  = 0.2215). There were also no significant differences between the fluoxetine and placebo groups in either study for changes in CDRS-R total score. Changes in CGI-S score were not significant between placebo and levomilnacipran 40 to 80 mg daily or between placebo and fluoxetine. Levomilnacipran was generally well tolerated. Conclusions: The high placebo response in this study prevented the detection of an effect of levomilnacipran in children and adolescents. Clinical Trial Registration numbers: NCT02431806 and NCT03569475.

Objective: Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome., Methods: Dravet mice of both sexes were evaluated for spontaneous seizure characterization and changes in SSIM incidence induced by agents that enhance 5-HT-mediated neurotransmission. Fluoxetine (a selective 5-HT reuptake inhibitor), fenfluramine (a 5-HT releaser and agonist), SR 57227 (a specific 5-HT 3 receptor agonist), or saline (vehicle) was intraperitoneally administered over an 8-day period in Dravet mice, and the effect of these treatments on SSIM was examined., Results: Spontaneous seizures in Dravet mice generally progressed from wild running to tonic seizures with or without SSIM. Fluoxetine at 30 mg/kg, but not at 20 or 5 mg/kg, significantly reduced SSIM compared with the vehicle control. Fenfluramine at 1-10 mg/kg, but not .2 mg/kg, fully protected Dravet mice from SSIM, with all mice surviving. Compared with the vehicle control, SR 57227 at 20 mg/kg, but not at 10 or 5 mg/kg, significantly lowered SSIM. The effect of these drugs on SSIM was independent of sex., Significance: Our data demonstrate that elevating serotonergic function by fluoxetine, fenfluramine, or SR 57227 significantly reduces or eliminates SSIM in Dravet mice in a sex-independent manner. These findings suggest that deficits in serotonergic neurotransmission likely play an important role in the pathogenesis of SSIM, and fluoxetine and fenfluramine, which are US Food and Drug Administration-approved medications, may potentially prevent SUDEP in at-risk patients., (© 2024 International League Against Epilepsy.)

The pre BCR complex plays a crucial role in B cell production, and its successful expression marks the B cell differentiation from the pro-B to pre-B. The CD79a and CD79b mutations, encoding Igα and Igβ respectively, have been identified as the cause of autosomal recessive agammaglobulinemia (ARA). Here, we present a case of a patient with a homozygous CD79a mutation, exhibiting recurrent respiratory infections, diarrhea, growth and development delay, unique facial abnormalities and microcephaly, as well as neurological symptoms including tethered spinal cord, sacral canal cyst, and chronic enteroviral E18 meningitis. Complete blockade of the early B cell development in the bone marrow of the patient results in the absence of peripheral circulating mature B cells. Whole exome sequencing revealed a Loss of Heterozygosity (LOH) of approximately 19.20Mb containing CD79a on chromosome 19 in the patient. This is the first case of a homozygous CD79a mutation caused by segmental uniparental diploid (UPD). Another key outcome of this study is the effective management of long-term chronic enteroviral meningitis using a combination of intravenous immunoglobulin (IVIG) and fluoxetine. This approach offers compelling evidence of fluoxetine's utility in treating enteroviral meningitis, particularly in immunocompromised patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in correlative studies in humans and causal studies in rodents. However, the contribution of the two distinct striatal output populations to the generation and treatment of compulsive behavior is unknown. These populations of direct and indirect pathway-projecting spiny projection neurons (SPNs) have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of direct relative to indirect pathway promotes compulsive behavior. Contrary to this hypothesis, here we find that indirect pathway hyperactivity is associated with compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. Furthermore, we show that suppression of indirect pathway activity using optogenetics or treatment with the first-line OCD pharmacotherapy fluoxetine is associated with reduced grooming in Sapap3-knockouts. Together, these findings highlight the striatal indirect pathway as a potential treatment target for compulsive behavior., (© 2024. The Author(s).)

Background: In Chagas disease (CD), a neglected tropical disease caused by the parasite Trypanosoma cruzi, the development of mental disorders such as anxiety, depression, and memory loss may be underpinned by social, psychological, and biological stressors. Here, we investigated biological factors underlying behavioral changes in a preclinical model of CD., Methodology/principal Findings: In T. cruzi-infected C57BL/6 mice, a kinetic study (5 to 150 days postinfection, dpi) using standardized methods revealed a sequential onset of behavioral changes: reduced innate compulsive behavior, followed by anxiety and depressive-like behavior, ending with progressive memory impairments. Hence, T. cruzi-infected mice were treated (120 to 150 dpi) with 10 mg/Kg/day of the selective serotonin reuptake inhibitor fluoxetine (Fx), an antidepressant that favors neuroplasticity. Fx therapy reversed the innate compulsive behavior loss, anxiety, and depressive-like behavior while preventing or reversing memory deficits. Biochemical, histological, and parasitological analyses of the brain tissue showed increased levels of the neurotransmitters GABA/glutamate and lipid peroxidation products and decreased expression of brain-derived neurotrophic factor in the absence of neuroinflammation at 150 dpi. Fx therapy ameliorated the neurochemical changes and reduced parasite load in the brain tissue. Next, using the human U-87 MG astroglioma cell line, we found no direct effect of Fx on parasite load. Crucially, serotonin/5-HT (Ser/5-HT) promoted parasite uptake, an effect increased by prior stimulation with IFNγ and TNF but abrogated by Fx. Also, Fx blocked the cytokine-driven Ser/5-HT-promoted increase of nitric oxide and glutamate levels in infected cells., Conclusion/significance: We bring the first evidence of a sequential onset of behavioral changes in T. cruzi-infected mice. Fx therapy improves behavioral and biological changes and parasite control in the brain tissue. Moreover, in the central nervous system, cytokine-driven Ser/5-HT consumption may favor parasite persistence, disrupting neurotransmitter balance and promoting a neurotoxic environment likely contributing to behavioral and cognitive disorders., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vilar-Pereira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Obsessive-compulsive disorder (OCD) is a pervasive disabling disorder that may overlap with other psychiatric conditions, including anorexia nervosa. Recent guidelines recommend low doses of second-generation antipsychotics as add-on therapy to selective serotonin reuptake inhibitors (SSRIs) for those patients presenting OCD who display residual symptomatology. Here we report a clinical case of a 45-years-old woman affected by severe OCD in comorbidity with anorexia nervosa, restrictive type (AN-r), treated with fluoxetine (titrated up to 40 mg/day) in augmentation with low doses of lurasidone (37 mg/day). At baseline and during a 6 months-follow-up we administered Clinical Global Impression-Severity, Symptom Checklist-90 items, Y-BOCS-II (Yale-Brown Obsessive Compulsive Scale) and EDI-3 (Eating Disorder Inventory). After 1 month of augmentation treatment, a clinically significant response was observed on obsessive symptoms at Y-BOCS-II (≥35% Y-BOCS reduction) and eating symptomatology at EDI-3. Full remission was reported after 3 months (Y-BOCS scoring ≤14) ( P  < 0.01). Further longitudinal and real-world effectiveness studies should be implemented to confirm these novel results, to investigate the potential of lurasidone as add-on strategy to SSRI in poor responder OCD patients, including treatment-resistant-OCD (tr-OCD), as well as in improving eating disorder symptomatology, whereas there is comorbidity with AN-r., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Study Aim: Distal esophageal spasm is an uncommon esophageal motility disorder presenting with non-cardiac chest pain and dysphagia. The main goal of therapy is symptom relief with pharmacologic, endoscopic, and surgical therapies. Pharmacologic treatment is less invasive and is the preferred method of choice. The purpose of this study was to compare the effectiveness of diltiazem versus fluoxetine in the treatment of distal esophageal spasm., Patients and Methods: A total of 125 patients with distal esophageal spasm diagnosed using endoscopy, barium esophagogram, and manometry were evaluated. Patients were divided into diltiazem and fluoxetine groups and received a 2-month trial of diltiazem + omeprazole or fluoxetine + omeprazole, respectively. Of 125 patients, 55 were lost to follow up and 70 were eligible for final analysis. Clinical signs and symptoms were assessed before and after therapy using four validated questionnaires: Eckardt score, short form-36, heartburn score, and the hospital anxiety and depression scale., Results: Both regimens significantly relieved symptoms (a decrease in mean Eckardt score of 2.57 and 3.18 for diltiazem and fluoxetine groups, respectively; and a decrease in mean heartburn score by 0.89 and 1.03 for diltiazem and fluoxetine groups, respectively). Patients' quality of life improved based on short form-36 (an increase in mean score of 2.37 and 3.95 for fluoxetine and diltiazem groups, respectively). There was no relationship between patients' improvement and severity of symptoms. Psychological findings based on the hospital anxiety and depression scale were inconsistent (a decrease in mean of 0.143 and 0.57 for fluoxetine and diltiazem groups, respectively; p > 0.05)., Conclusion: Fluoxetine and diltiazem were effective for clinical symptom relief in patients with distal esophageal spasm, but were not promising for improving psychological symptoms. Neither regimen was superior in terms of efficacy. Consequently, it is key to consider side effects and comorbidities when choosing a therapy., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Background: Cerebellar mutism syndrome (CMS) occurs in 8-29 % of children undergoing posterior fossa tumor surgery. Its main symptoms are mutism and emotional lability. Although it is always transient, recovery time can be lengthy with long-term cognitive sequelae. There is no approved drug treatment for CMS, but some drugs are used in everyday medical practice. One of these is fluoxetine, which has been used for many years in our institution. The main objective of this study was to establish the safety profile of fluoxetine in this condition., Materials and Methods: The records of patients admitted to the pediatric intensive care unit after brain surgery at Angers University Hospital from 2010 to 2020 were reviewed. Children aged 2 years and older who underwent a posterior fossa tumor surgery and were diagnosed with CMS were included. Data on patient characteristics, prescription of fluoxetine treatment, side effects if any, and complete mutism duration were collected., Results: Among 246 patients admitted to the pediatric intensive care unit for brain surgery during the study period, 23 had CMS and eight were prescribed fluoxetine. No serious adverse event related to fluoxetine was reported. Complete mutism duration did not differ significantly between the fluoxetine group and the non-fluoxetine group(p = 0.22). However, the treatment was initiated after recovery from complete mutism in half of the treated patients., Conclusion: This study suggests a positive safety profile of fluoxetine used in postoperative CMS. It does not answer the question of whether the treatment is effective for this indication. A randomized controlled trial based on a syndrome severity scale should be conducted to provide a more reliable assessment of the efficacy and safety of fluoxetine., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Objective: We evaluated the presence and impact of unblinding during the influential Treatment for Adolescents with Depression Study (ClinicalTrials.gov Identifier: NCT00006286)., Method: Our analysis was part of a Restoring Invisible and Abandoned Trials reanalysis. Treatment for Adolescents with Depression Study trialled fluoxetine, placebo, cognitive behaviour therapy or their combination, in treating adolescents with major depressive disorder. We analysed the accuracy of guesses of fluoxetine or placebo allocation, and their effects on change in Children's Depression Rating Scale-Revised at 12 weeks., Results: Of 221 participants allocated to fluoxetine or placebo, 151 adolescents (68%) had their guess about pill-treatment-arm allocation recorded at week 6, and guesses were recorded for 154 independent evaluators, 159 parents and 164 pharmacotherapists. All of these groups guessed treatment allocation more accurately than would be expected by chance (60-66% accuracy; all p -values ⩽ 0.004). Guesses did not become more accurate between 6 and 12 weeks and were not predicted by adverse events, though event documentation was poor. Treatment guess had a substantial and statistically significant effect on outcome (Children's Depression Rating Scale-Revised change mean difference 9.12 [4.69; 13.55], β = 0.334, p < 0.001), but actual treatment arm did not (1.53 [-2.83; 5.89], β = 0.056, p = 0.489). Removing guess from the analysis increased the apparent effect of treatment arm, making it almost statistically significant at the conventional alpha-level of 0.05 ( p = 0.06)., Conclusions: For Treatment for Adolescents with Depression Study, treatment guesses strongly predicted outcomes and may have led to the exaggeration of drug effectiveness in the absence of actual effects. The integrity of double-blinding in trials should be routinely assessed and reported., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: J.J. affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. J.M. is involved in grant-funded research on methods to reduce antidepressants, receives royalties from books on psychiatric drugs and is co-chair person of the unfunded Critical Psychiatry Network.

Background: The effects of the selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressant treatment, have been proposed to be affected, at least in part, by the living environment. Since the quality of the environment depends not only on its objective features, but also on the subjective experience, we hypothesized that the latter plays a key role in determining SSRI treatment outcome., Methods: We chronically administered the SSRI fluoxetine to two groups of adult CD-1 male mice that reportedly show distinct subjective experiences of the environment measured as consistent and significantly different responses to the same emotional and social stimuli. These distinct socioemotional profiles were generated by rearing mice either in standard laboratory conditions (SN) or in a communal nest (CN) where three dams breed together their offspring, sharing caregiving behavior., Results: At adulthood, CN mice displayed higher levels of agonistic and anxiety-like behaviors than SN mice, indicating that they experience the environment as more socially challenging and potentially dangerous. We then administered fluoxetine, which increased offensive and anxious response in SN, while producing opposite effects in CN mice. BDNF regulation was modified by the treatment accordingly., Limitations: Subjective experience in mice was assessed as behavioral response to the environment., Conclusions: These results show that the subjective experience of the environment determines fluoxetine outcome. In a translational perspective, our findings suggest considering not only the objective quality, but also the subjective appraisal, of the patient's living environment for developing effective personalized therapeutic approaches in psychiatry., Competing Interests: Declaration of competing interest All authors reported no interests or potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Selective serotonin (5-HT) reuptake inhibitors are only 30% effective for remission in subjects with major depression, and the best treatments for SSRI-resistant patients remain unclear. To model SSRI resistance, we used cF1ko mice with conditional deletion of the repressor Freud-1/CC2D1A in adult 5-HT neurons. Within weeks, this deletion leads to overexpression of 5-HT1A autoreceptors, reduced serotonergic activity, and fluoxetine-resistant anxiety-depression phenotype. We hypothesized that desipramine (DES), which targets norepinephrine (NE), may be effective in cF1ko mice. The actions of chronic DES treatment on behavior, chronic cellular activation, and NE projections were examined in both sexes of cF1ko and WT mice. In contrast to fluoxetine, chronic DES reversed the behavioral phenotypes in cF1ko mice, while in WT littermates DES slightly increased anxiety and depression-like behaviors. Deficits in FosB+ cell counts were seen in the entorhinal cortex, hippocampal CA2/3 layer, and BLA of cF1ko mice and were reversed by chronic DES treatment, especially in GABAergic neurons. In cF1ko mice, widespread reductions were seen in NE axons, varicosities, and especially 30-60% reductions in NE synaptic and triadic contacts, particularly to inhibitory gephyrin-positive sites. DES treatment also reversed these reductions in NE innervation. These results indicate the dynamic plasticity of the adult noradrenergic system within weeks of altering serotonergic function that can be normalized by DES treatment. Accompanying these changes, DES but not fluoxetine reversed the behavioral alterations in cF1ko mice, suggesting a key role for noradrenergic plasticity in antidepressant response in this model of reduced serotonin activity., (Copyright © 2024 the authors.)

Background: Pro-inflammatory cytokines are implicated in depression caused by both environmental- and alcohol-induced stress. The purpose of the study was to investigate the cytokine levels in serum and hippocampus following induction of depression-like behaviors (DLB) by either forced swimming test (FST) or ethanol-induced DLB (EID). We also investigated the effect of prior administration of antidepressant drug fluoxetine on cytokines in animals exposed to both models of DLB. Methods: Animals were pretreated with fluoxetine before inducing DLB, while DLB was induced in some animals using FST and ethanol in different groups of rats without fluoxetine pretreatment. The ELISA was used to detect changes in cytokine (IL-1β, IL-6, and TNF-α) levels in serum and hippocampus. Results: The mean levels of IL-1β and IL-6 measured in serum and hippocampus were significantly higher in FST and EID models when compared to the control group. The serum concentrations of IL-1β and IL-6 were significantly reduced in animals pre-treated with 5 mg/kg and 10 mg/kg of fluoxetine in both FST and EID models when compared to the untreated FST and EID groups respectively. Conclusions: In conclusion, both environment and alcohol can induce stress and DLB in rats with similar intensity, and their mechanisms of DLB induction involve activation of pro-inflammatory cytokines. Moreover, fluoxetine can prevent stress-induced inflammation in models of DLB., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Emotion regulation deficits are characteristic of youth depression and are underpinned by altered frontoamygdalar function. However, the causal dynamics of frontoamygdalar pathways in depression and how these dynamics relate to treatment prognosis remain unexplored. This study aimed to assess frontoamygdalar effective connectivity during cognitive reappraisal in youths with depression and to test whether pathway dynamics are predictive of individual response to combined cognitive behavioral therapy plus treatment with fluoxetine or placebo., Methods: One hundred seven young people with moderate to severe depression and 94 healthy control participants completed a functional magnetic resonance imaging cognitive reappraisal task. After the task, 87 participants with depression were randomized and received 12 weeks of cognitive behavioral therapy plus either fluoxetine or placebo. Dynamic causal modeling was used to map frontoamygdalar effective connectivity during reappraisal and to assess the predictive capacity of baseline frontoamygdalar effective connectivity on depression diagnosis and posttreatment depression remission., Results: Young people with depression showed weaker inhibitory modulation of ventrolateral prefrontal cortex to amygdala connectivity during reappraisal (0.29 Hz, posterior probability = 1.00). Leave-one-out cross-validation demonstrated that this effect was sufficiently large to predict individual diagnostic status (r = 0.20, p = .003). Posttreatment depression remission was associated with weaker excitatory ventromedial prefrontal cortex to amygdala connectivity (-0.56 Hz, posterior probability = 1.00) during reappraisal at baseline, though this effect did not predict individual remission status (r = -0.02, p = .561)., Conclusions: Frontoamygdalar effective connectivity shows promise in identifying youth depression diagnosis, and circuits responsible for negative affect regulation are implicated in responsiveness to first-line depression treatments., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

This study investigates the therapeutic potential of a new compound, potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (Compound I ), in depression. Willner's chronic unpredictable mild stress model of male Wistar rats was used as a depression model. The rats were randomized into four groups, including an intact group, a Compound I group, a Fluoxetine group, and a control group with saline. Behavioral tests, such as the Porsolt forced swim test, hole-board test, elevated plus maze test, and light-dark box, were used to assess the animals' conditions. Our results demonstrated that Compound I effectively reduced the immobilization time of rats in the forced swim test, increased orientation and exploratory behavior, and decreased the latency period of going into the dark compartment compared to the control group. Hippocampal and striatal serotonin concentrations were increased in the Compound I group, and the compound also reduced the level of corticosterone in the blood plasma of rats compared to the intact animals. These results suggest that Compound I has reliable antidepressant activity, comparable to that of the reference antidepressant Fluoxetine.

Introduction: The neuroactive metabolite of progesterone, allopregnanolone (ALLO), has been implicated in premenstrual syndrome (PMS) physiopathology and preclinical studies suggested that low doses of fluoxetine increase the ALLO brain concentration., Objectives: To assess which low dose of fluoxetine (2 mg/d, 5 mg/d or 10 mg/d), administered exclusively during the luteal phase of menstrual cycle, has a potential effect for preventing or mitigating emotional PMS symptoms., Methods: In this randomized, double-blind, placebo-controlled pilot study, we followed 40 women (mean age = 29.7 +/- 7.4 years) with emotional PMS, during two menstrual cycles: cycle 1, without pharmacological intervention; and cycle 2, with pharmacological intervention. Participants took capsules, on average, seven days preceding the likely date of menses. We assessed the severity of PMS symptoms in both cycles using the Daily Record of Severity of Problems scale (DRSP)., Results: There was an increase in the DRSP scores during the late luteal phase of cycle 1, confirming the diagnosis of emotional PMS. Low doses of fluoxetine (5 mg/d: 33.5%; 10 mg/d: 48.4%) reduced DRSP total score in the day before menses (day-1) at cycle 2 compared with day-1 at cycle 1. Fluoxetine 10 mg/d had the most consistent decline in emotional PMS symptoms; 70% of the participants reported a reduction greater than 40% in the DRSP score., Conclusions: Low doses of fluoxetine, which may have no or few effect on the serotonergic system, but may interfere in the progesterone metabolization, seem to have some potential to mitigate emotional PMS symptoms. While the 10 mg/d of fluoxetine had the best performance on reducing emotional PMS symptoms, the 5 mg/d dose also seems to have some effect on emotional PMS symptoms. Further larger studies will help establish the lowest effective dose of flouxetine for PMS treatment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The peripartal period is marked by alterations in calcium metabolism to accommodate for embryonic skeletal mineralization and support bone development of offspring in early life, and serotonin plays a critical role in modulating peripartal bone remodeling. Selective serotonin reuptake inhibitors (SSRIs) are commonly used as first-line treatment for psychiatric illness during pregnancy and the postpartum period and considered safe for maternal use during this time frame. In order to evaluate the effect of peripartal alterations of the serotonergic system on maternal skeletal physiology, we treated dams with the SSRI fluoxetine during gestation only, lactation only, or during the entire peripartal period. Overall, we found a low dose of fluoxetine during gestation only had minimal impacts on maternal bone at weaning, but there were implications on maternal skeleton at weaning when dams were exposed during lactation only or during the entire peripartal period. We found that these effects were differential between female mice dosed lactationally or peripartally, and there were also impacts on maternal mammary gland at weaning in both of these groups. Though SSRIs are largely considered safe maternally during the peripartal period, this study raises the question whether safety of SSRIs, specifically fluoxetine, during the peripartal period should be reevaluated., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Depression is a mood disorder coursing with several behavioral, cellular, and neurochemical alterations. The negative impact of chronic stress may precipitate this neuropsychiatric disorder. Interestingly, downregulation of oligodendrocyte-related genes, abnormal myelin structure, and reduced numbers and density of oligodendrocytes in the limbic system have been identified in patients diagnosed with depression, but also in rodents exposed to chronic mild stress (CMS). Several reports have emphasized the importance of pharmacological or stimulation-related strategies in influencing oligodendrocytes in the hippocampal neurogenic niche. Repetitive transcranial magnetic stimulation (rTMS) has gained attention as an intervention to revert depression. Here, we hypothesized that 5 Hz (Hz) of rTMS or Fluoxetine (Flx) would revert depressive-like behaviors by influencing oligodendrocytes and revert neurogenic alterations caused by CMS in female Swiss Webster mice. Our results showed that 5 Hz rTMS or Flx revert depressive-like behavior. Only rTMS influenced oligodendrocytes by increasing the number of Olig2-positive cells in the hilus of the dentate gyrus and the prefrontal cortex. However, both strategies exerted effects on some events of the hippocampal neurogenic processes, such as cell proliferation (Ki67-positive cells), survival (CldU-positive cells), and intermediate stages (doublecortin-positive cells) along the dorsal-ventral axis of this region. Interestingly, the combination of rTMS-Flx exerted antidepressant-like effects, but the increased number of Olig2-positive cells observed in mice treated only with rTMS was canceled. However, rTMS-Flx exerted a synergistic effect by increasing the number of Ki67-positive cells. It also increased the number of CldU- and doublecortin-positive cells in the dentate gyrus. Our results demonstrate that 5 Hz rTMS has beneficial effects, as it reverted depressive-like behavior by increasing the number of Olig2-positive cells and reverting the decrement in hippocampal neurogenesis in CMS-exposed mice. Nevertheless, the effects of rTMS on other glial cells require further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was financially supported by INPRFM (SIC-2000) to GBRR. The equipment for this study was kindly financed by CONACYT (Grant Infraestructura 2015; 254773 to GBRR). INPRFM and CONACYT did not influence on the decision to publish the results included in this manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This article aimed to investigate the effects of Haplophyllum robustum hydroalcoholic extract on animals' behavioral and electrocorticographic changes. This plant is mainly found in Turkey, Iran, and Central Asia, and is reported to have convulsive effects. In this article, we worked on the effects of its hydroalcoholic extract on electrocorticography (ECoG), along with changes induced by intracerebroventricular administration of GABA A antagonists. Furthermore, the effects of low doses of this extract on behavioral depression were examined. Four animal sets were used to compare ECoG in Wistar rats. A group of negative control, a group of positive control (PTZ), and two groups received an injection of plant extract (500 mg/kg, ip), with or without administration of Diazepam (5 mg/kg). Also, three sets were applied to compare receiving and not receiving intracerebroventricular (icv) injection of Transient receptor potential ankyrin 1 antagonist (HC-030031) (2 μg/kg) on plant-induced seizure delay and animal death. Two groups of control and a group with plant extract together with TRPA1 antagonist were administrated. Furthermore, in the present study, the forced swimming test (FST) was used as a model of depression. The behaviors of animals in three groups of negative control and positive control (Fluoxetine) and plant extract (200 mg/kg, ip) were compared. According to the ECoG, high doses of extract of plants led to seizures similar to PTZ, which were then reduced by diazepam injection. At this dose, injection of TRPA1 antagonist did not significantly delay the onset of seizures or the death of the animals. Further, a subconvulsive dose of hydroalcoholic plant extracts was equally effective in treating depression as Fluoxetine injections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Escitalopram, fluoxetine, and amitriptyline are the drugs commonly used in the treatment of depression. The pharmacoeconomic evaluation of these drugs becomes relevant as they are prescribed for a long period of time, and depression causes a significant economic burden. The cost-minimization study would contribute to bringing down the annual treatment costs, leading to better medication adherence and ultimately better patient outcomes., Materials and Methods: All drug prices are mentioned in Indian National Rupee (INR). All expenses are based on 2022 pricing. No cost discounting was used because all expenditures were calculated over a year. We considered hypothetical scenarios where the patient was prescribed the lowest possible dose for depression, an equivalent antidepressant dose, a defined daily dose, and the maximum acceptable therapeutic dose for depression., Results: Annual average treatment costs of amitriptyline, escitalopram, and fluoxetine in patients with depression at baseline with equivalent dosing as mono-drug therapy were 2765.53, 2914.78, and 1422.72 rupees (INR), respectively. Savings were high when the patient was shifted to fluoxetine from either escitalopram or amitriptyline. The savings from switching to fluoxetine were 50.66% and 56.42% from escitalopram and amitriptyline, respectively., Conclusion: The choice of an antidepressant depends on multiple aspects, among which the cost of treatment plays a crucial role. Among the drugs compared, fluoxetine seems to offer greater value for money. The study emphasizes that selective serotonin reuptake inhibitors are the most commonly prescribed antidepressants not only because of their favorable pharmacological profile but also because of their affordability., Competing Interests: None

Objectives: Reboxetine is a potent and selective norepinephrine reuptake inhibitor that was effective in combination with citalopram for resistant obsessive-compulsive disorder (OCD). This study aims to assess its effectiveness and tolerability in combination with fluoxetine in treating OCD., Methods: In this 2-center, placebo-controlled, and double-blind, randomized clinical trial, 76 patients with OCD were assigned into 2 parallel groups to receive fluoxetine (up to 80 mg/d) plus placebo (F + P) or fluoxetine (up to 80 mg/d) plus reboxetine (F + R) (10 mg twice daily) for 10 weeks. Participants were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and weeks 5 and 10., Results: A total of 76 patients completed the trial. There was no significant difference between the 2 groups in baseline Y-BOCS scores. General linear model repeated-measures showed significant effects on time × treatment interaction on total Y-BOCS ( F = 6.33, df = 1.42, P = 0.006) and obsession subscale scores ( F = 10.39, df = 1.48, P < 0.001), and insignificance on compulsion subscale scores ( F = 1.86, df = 1.24, P = 0.173). Reboxetine combination therapy demonstrated a higher partial and complete treatment response rate ( P < 0.01) according to the Y-BOCS total scores. There was no significant difference between the 2 groups in the frequency of adverse effects., Conclusions: Reboxetine combination therapy with fluoxetine can effectively improve symptoms in patients with OCD in a short period of treatment. However, further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings.This trial was registered with the Iranian Registry of Clinical Trials ( www.irct.ir ; No IRCT20090117001556N129)., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare. This study was funded by Tehran University of Medical Sciences and Health Services (grant number: 45986)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The vagus nerve is a major pathway in the body that is responsible for regulating the activity of the parasympathetic nervous system, which plays an important role in mood disorders including anxiety and depression. Fluoxetine, also known as Prozac, is widely used to treat depression. Nevertheless, there are few studies on the vagus nerve-mediated action of fluoxetine. In this study, we aimed to investigate the vagus nerve-dependent actions of fluoxetine in mice with restraint stress-induced or antibiotics-induced anxiety- and depression-like behaviors. Compared to sham operation, vagotomy alone did not exhibit significant effects on behavioral changes and serotonin-related biomarkers in mice not exposed to stress, antibiotics, or fluoxetine. Oral administration of fluoxetine significantly alleviated anxiety- and depression-like behaviors. However, celiac vagotomy significantly attenuated the anti-depressive effects of fluoxetine. The vagotomy also inhibited the effect of fluoxetine to attenuate restraint stress- or cefaclor-induced reduction in serotonin levels and Htr1a mRNA expression in the hippocampus. These findings suggest that the vagus nerve may regulate the efficacy of fluoxetine for depression., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: Depression is a disorder twice as common in women than in men. There are sex differences in the symptomatology and treatment response to this disorder. Impairments in behavioral activation (i.e. anergia, fatigue) are often seen in people with depression and are highly resistant to treatment. The role of mesolimbic dopamine (DA) in regulating behavioral activation has been extensively studied in male rodents, but little is known in female rodents., Objective: The present studies assessed potential sex differences in rodent paradigms used to study different components of depressive-like behavior, and in the treatment response to antidepressants with different mechanisms of action., Methods: Male and female CD1 mice received Tetrabenazine (TBZ), a VMAT-2 blocker that depletes DA and induces depressive symptoms in humans. Mice were tested on the Forced Swim Test, (FST), the Dark-Light box (DL), the elevated plus maze (EPM), Social Interaction (SI) test, and sucrose preference and consumption using the two bottles test. In addition, bupropion (a DA reuptake inhibitor) or fluoxetine (a serotonin reuptake inhibitor) were used to reverse TBZ-induced anergia., Results: In the FST, bupropion reversed TBZ effects in both sexes but fluoxetine was only effective in female mice. DA depletion did not affect other aspects of depression such as anxiety, sociability or sucrose consumption, and there was no interaction with bupropion on these parameters. In TBZ treated-females SERT-blockers may be effective at reversing anergia in aversive contexts (FST), and potentiating avoidance of anxiogenic stimuli., Conclusions: Pro-dopaminergic antidepressants seem more efficacious at improving anergia in both sexes than SERT-blockers., (© 2023. The Author(s).)

Background: Fluoxetine is one of the selective serotonin reuptake inhibitors that can improve motor and function recovery after a stroke. Several randomized controlled trials (RCTs) have investigated the efficacy and safety of fluoxetine compared to placebo in post-stroke recovery. However, the results are still controversial., Aim: This meta-analysis aimed to provide an updated analysis of the efficacy and safety of fluoxetine versus placebo in post-stroke recovery., Method: RCTs were searched from electronic databases of PubMed, Embase, Clinical Trials, and the Cochrane Central Register of Controlled Trials from inception until July 2022. Google Scholar and the reference lists of included studies were screened to identify additional studies. Outcomes were analyzed using risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI)., Results: Fourteen RCTs (6584 patients) were included. The fluoxetine group showed a significantly higher Fugl-Meyer motor scale (FMMS) score than the placebo group (MD 15.93, 95%CI 9.76-22.7, P < 0.01). No significant differences were observed in the modified Rankin Scale (mRS) (mRS ≤ 2, RR 1.00, 95%CI 0.88-1.15, P = 0.95), the Barthel index (MD 12.11, 95%CI - 0.71 to 24.92, P = 0.06), and the National Institutes of Health Stroke Scale scores (MD - 0.19, 95%CI - 0.43 to 0.04, P = 0.1) between the two groups. The fluoxetine group showed a lower rate of depression or anxiety than the placebo group (RR 0.67, 95% CI 0.49-0.92, P < 0.05). There were no significant differences between the groups regarding gastrointestinal adverse reactions (P > 0.05), drowsiness (P > 0.05) or insomnia (P > 0.05)., Conclusion: Fluoxetine improved FMMS and reduced anxiety and depression. More well-designed and large sample-size RCTs are required to further analyze the efficacy of fluoxetine in post-stroke recovery., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cerebral palsy (CP) is characterized by motor disorders, including deficits in locomotor activity, coordination, and balance. Selective serotonin reuptake inhibitors have been shown to play an important role in brain plasticity. This study investigates the effect of neonatal treatment using fluoxetine on locomotor activity and histomorphometric parameters of the primary somatosensory cortex (S1) in rats submitted to an experimental model of CP. CP was found to reduce bodyweight and locomotion parameters and also to increase the glia/neuron index in the S1. Administration of fluoxetine 10 mg/kg reduced bodyweight, impaired locomotor activity parameters, and increased the number of glial cells and the glia/neuron ratio in the S1 in rats with CP. However, treatment with fluoxetine 5 mg/kg was not found to be associated with adverse effects on locomotor activity and seems to improve histomorphometric parameters by way of minor changes in the S1 in animals with CP. These results thus indicate that experimental CP, in combination with the use of a high dose of fluoxetine (10 mg/kg), impairs locomotor and histomorphometric parameters in the S1, while treatment with a low dose of fluoxetine (5 mg/kg) averts the negative outcomes associated with a high dose of fluoxetine in relation to these parameters but produces no protective effect., Competing Interests: The authors declare there are no competing interests.

The increasing prevalence of depression requires more effective therapy and the understanding of antidepressants' mode of action. We carried out untargeted metabolomics of the prefrontal cortex of rats exposed to chronic social isolation (CSIS), a rat model of depression, and/or fluoxetine treatment using liquid chromatography-high resolution mass spectrometry. The behavioral phenotype was assessed by the forced swim test. To analyze the metabolomics data, we employed univariate and multivariate analysis and biomarker capacity assessment using the receiver operating characteristic (ROC) curve. We also identified the most predictive biomarkers using a support vector machine with linear kernel (SVM-LK). Upregulated myo-inositol following CSIS may represent a potential marker of depressive phenotype. Effective fluoxetine treatment reversed depressive-like behavior and increased sedoheptulose 7-phosphate, hypotaurine, and acetyl-L-carnitine contents, which were identified as marker candidates for fluoxetine efficacy. ROC analysis revealed 4 significant marker candidates for CSIS group discrimination, and 10 for fluoxetine efficacy. SVM-LK with accuracies of 61.50% or 93.30% identified a panel of 7 or 25 predictive metabolites for depressive-like behavior or fluoxetine effectiveness, respectively. Overall, metabolic fingerprints combined with the ROC curve and SVM-LK may represent a new approach to identifying marker candidates or predictive metabolites for ongoing disease or disease risk and treatment outcome.

The recombinant B6.CBA-D13Mit76C mouse strain is characterized by an altered sensitivity of 5-HT 1A receptors and upregulated 5-HT 1A gene transcription. Recently, we found that in B6.CBA-D13Mit76C mice, chronic fluoxetine treatment produced the pro-depressive effect in a forced swim test. Since 5-HT 2A receptor blockade may be beneficial in treatment-resistant depression, we investigated the influence of chronic treatment (14 days, intraperitoneally) with selective 5-HT 2A antagonist ketanserin (0.5 mg/kg), fluoxetine (20 mg/kg), or fluoxetine + ketanserin on the behavior, functional activity of 5-HT 1A and 5-HT 2A receptors, serotonin turnover, and transcription of principal genes of the serotonin system in the brain of B6.CBA-D13Mit76C mice. Ketanserin did not reverse the pro-depressive effect of fluoxetine, while fluoxetine, ketanserin, and fluoxetine + ketanserin decreased the functional activity of 5-HT 1A receptors and Htr1a gene transcription in the midbrain and hippocampus. All tested drug regimens decreased the mRNA levels of Slc6a4 and Maoa in the midbrain. These changes were not accompanied by a significant shift in the levels of serotonin and its metabolite 5-HIAA. Notably, ketanserin upregulated enzymatic activity of tryptophan hydroxylase 2 (TPH2). Thus, despite some benefits (reduced Htr1a, Slc6a4, and Maoa transcription and increased TPH2 activity), prolonged blockade of 5-HT 2A receptors failed to ameliorate the adverse effect of fluoxetine in the case of abnormal functioning of 5-HT 1A receptors.

Introduction: Selective serotonin reuptake inhibitors are considered the drugs, whose effectiveness in viral pandemics has been studied. The aim of this study was to evaluate of adding fluoxetine to the treatment regimen of patients with COVID-19 pneumonia., Methods: This study was a double-blind randomized placebo controlled clinical trial .36 patients in the fluoxetine and 36 patients in the placebo group were enrolled. Patients in the intervention group were first treated with fluoxetine 10 mg for 4 days and then the dose of 20 mg was continued for 4 weeks. Data analysis was conducted using SPSS V. 22.0., Results: There was no statistically significant difference between the two groups in terms of clinical symptoms at the beginning of the study and also the score of anxiety and depression, oxygen saturation at the time of hospitalization, mid-hospitalization and discharge periods. The need for mechanical ventilator support (p = 1.00), the need for admission in the intensive care unit (ICU) (p = 1.00), rate for mortality (p = 1.00), and discharge with relative recovery (p = 1.00) were not significantly different between the two groups. The distribution of CRP within the study groups showed a significant decrease during different time periods (p = 0.001), and although there was no statistically significant difference between the two groups on the first day (p = 1.00) and at discharge (p = 0.585), mid-hospital CRP showed a significant decrease in the fluoxetine group (p = 0.032)., Conclusion: Fluoxetine resulted in a faster reduction of patients' inflammation without association with depression and anxiety., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Objective: We searched for, from the FDA (Food and Drug Administration-USA)-approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (eg, mild headache, sedation, etc.) and with the ability to cross the blood brain barrier (BBB), using bio-informatics tools (in-silico). This may pave the road for designing clinical trials of such drugs in patients with functional seizures (FS) and other stress-associated disorders., Methods: Several databases were used to find all the approved drugs that potentially have interactions with FKBP51 protein [ie, CTD gene-chemical interaction section of FKBP51 protein of Harmonizome of Mayaanlab, DrugCenteral database, PDID (Protein Drug Interaction Database), DGIdb (the Drug Gene Interaction database)]. Other databases were also searched [eg, clinicaltrials.gov; DRUGBANK (the FASTA format of the FKBP51 protein was imported to the target sequencing section of the database to find the associated drugs), and the STITCH database (to find the related chemical interaction molecules)]., Results: After a comprehensive search of the designated databases, 28 unique and approved drugs were identified. Fluticasone propionate and Mifepristone and Ponatinib, Mirtazapine, Clozapine, Enzalutamide, Sertraline, Prednisolone, Fluoxetine, Dexamethasone, Clomipramine, Duloxetine, Citalopram, Chlorpromazine, Nefazodone, and Escitalopram are inhibitors of FKBP5 and have BBB permeability., Significance: While the current in-silico repurposing study could identify potential drugs (that are already approved and are widely available) for designing clinical trials in patients with stress-associated disorders (eg, FS), any future clinical trial should consider the pharmacological profile of the desired drug and also the characteristics and comorbidities of the patients in order to foster a success., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To investigate the role of hippocampal neurodevelopment in the antidepressant effect of baicalin., Methods: Forty male Institute of Cancer Research mice were divided into control, corticosterone (CORT, 40 mg/kg), CORT+baicalin-L (25 mg/kg), CORT+baicalin-H (50 mg/kg), and CORT+fluoxetine (10 mg/kg) groups according to a random number table. An animal model of depression was established by chronic CORT exposure. Behavioral tests were used to assess the reliability of depression model and the antidepressant effect of baicalin. In addition, Nissl staining and immunofluorescence were used to evaluate the effect of baicalin on hippocampal neurodevelopment in mice. The protein and mRNA expression levels of neurodevelopment-related factors were detected by Western blot analysis and real-time polymerase chain reaction, respectively., Results: Baicalin significantly ameliorated the depressive-like behavior of mice resulting from CORT exposure and promoted the development of dentate gyrus in hippocampus, thereby reversing the depressive-like pathological changes in hippocampal neurons caused by CORT neurotoxicity. Moreover, baicalin significantly decreased the protein and mRNA expression levels of glycogen synthase kinase 3β (GSK3β), and upregulated the expression levels of cell cycle protein D1, p-mammalian target of rapamycin (mTOR), doublecortin, and brain-derived neurotrophic factor (all P<0.01). There were no significant differences between baicalin and fluoxetine groups (P>0.05)., Conclusion: Baicalin can promote the development of hippocampal neurons via mTOR/GSK3β signaling pathway, thus protect mice against CORT-induced neurotoxicity and play an antidepressant role., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Accumulating evidence has revealed an association between depression and disordered intestinal microecology. The discovery of psychobiotics has provided a promising perspective for studying the treatment of psychiatric disorders. Here, we aimed to investigate the antidepressant abilities of Lactocaseibacillus rhamnosus zz-1 (LRzz-1) and elucidate the underlying mechanisms. The viable bacteria (2 × 10 9 CFU/day) were orally supplemented to depressed C57BL/6 mice induced by chronic unpredictable mild stress (CUMS), and the behavioral, neurophysiological, and intestinal microbial effects were assessed, with fluoxetine used as a positive control. The treatment with LRzz-1 effectively mitigated the depression-like behavioral disorders of depressed mice and reduced the expression of inflammatory cytokine mRNA (IL-1β, IL-6, and TNF-α) in the hippocampus. In addition, LRzz-1 treatment also improved tryptophan metabolic disorder in the mouse hippocampus, as well as its peripheral circulation. These benefits are associated with the mediation of microbiome-gut-brain bidirectional communication. CUMS-induced depression impaired the intestinal barrier integrity and microbial homeostasis in mice, neither of which was restored by fluoxetine. LRzz-1 prevented intestinal leakage and significantly ameliorated epithelial barrier permeability by up-regulating tight-junction proteins (including ZO-1, occludin, and claudin-1). In particular, LRzz-1 improved the microecological balance by normalizing the threatened bacteria (e.g., Bacteroides and Desulfovibrio ), exerting beneficial regulation (e.g., Ruminiclostridium 6 and Alispites ), and modifying short-chain fatty acid metabolism. In summary, LRzz-1 showed considerable antidepressant-like effects and exhibited more comprehensive intestinal microecological regulation than other drugs, which offers novel insights that can facilitate the development of depression therapeutic strategies.

Rationale: Characterizing the neuroanatomical basis of serotonergic abnormalities in severe, chronic, impulsive aggression will allow for rational treatment selection, development of novel therapeutics, and biomarkers to identify at-risk individuals., Objectives: The aim of this study is to identify associations between regional serotonin transporter (5-HTT) availability and trait and state aggression, as well as response to the anti-aggressive effects of fluoxetine., Methods: We examined 5-HTT availability using positron emission tomography (PET) imaging with [ 11 C]DASB in personality disordered patients with current physical intermittent explosive disorder (IED; n = 18), and healthy comparison participants (HC; n = 11), in the anterior cingulate cortex (ACC), amygdala (AMY), ventral striatum (VST), and midbrain (MID). After PET imaging, IED patients were treated with fluoxetine 20 mg daily (n = 9) or placebo (n = 6) for 12 weeks. Trait and state aggression, trait callousness, and childhood trauma were assessed., Results: In IED patients, trait aggression was positively associated with [ 11 C]DASB binding in the ACC and VST; covarying for trait callousness and childhood trauma enhanced these correlations. Baseline state aggression was positively correlated with ACC [ 11 C]DASB in IED patients. Greater baseline VST [ 11 C]DASB binding predicted greater decreases in state aggression with fluoxetine treatment., Conclusions: Consistent with prior reports, ACC 5-HTT is related to trait aggression, and adjusting for factors related to proactive (callousness) and reactive (childhood trauma) aggression subtypes further resolves this relationship. Novel findings of the study include a better understanding of the association between regional 5-HTT availability and state aggression, and the involvement of VST 5-HTT with trait aggression, and with the anti-aggressive effects of fluoxetine., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Methylphenidate (MP) is frequently prescribed to treat Attention-Deficit/Hyperactivity Disorder (ADHD); however, many patients with ADHD experience depression and anxiety. As such, concomitant administration of selective serotonin reuptake inhibitors such as fluoxetine (FLX) is common. Our laboratory and others have shown that MP impairs skeletal development in preclinical and clinical settings, and FLX has also been linked to skeletal deficits. Unfortunately, little is known about the effects of combined MP and FLX treatment on skeletal development. The objective of this study was to investigate the effects of MP and FLX on bone morphology and biomechanical properties in adolescent rats. Four-week-old male Sprague-Dawley rats were randomly divided into the following 4 groups: Water, MP, FLX, and MP + FLX. As body weights in the MP, FLX, and MP + FLX groups were all lower than Water, the data were compared directly and after adjusting to body weight via linear regression. The direct comparison revealed that MP + FLX rats had significantly shorter (~12 %) and narrower femora and tibiae (~10 %) compared to most other groups, along with shorter (26-35 %), disorganized tibial growth plates. MicroCT analyses of the trabecular compartment of the proximal tibia identified reductions of 47 % for TV, 86 % for BV, 74 % for BV/TV, 68 % for Tb.N, 25 % in Tb.Th, and 74 % in vBMD concomitant with increases of 44 % for Tb.Sp for MP + FLX compared to Water. Similar analyses of femoral midshaft cortical bone identified reductions of 29 % for Ct.V, 30 % for Ps.V, 30 % for Ec. V, and 51 % for pMOI, as well as increases of 17 % for Ct.Th and 2 % for TMD for MP + FLX compared to Water. Biomechanically, MP + FLX femora were weaker, as indicated by a reduction in ultimate force (14 %) in MP + FLX compared to Water. The microstructural and biomechanical effects of MP + FLX were eliminated after adjustment for body weight, though the detrimental effects on growth plate morphology remained. We conclude that while the adverse microstructural and biomechanical effects of MP + FLX seen via direct comparison are predominantly attributable to reductions in body weight rather than direct effects on bone, MP and FLX, particularly in combination show detrimental effects on growth plate structure and chondrocyte morphology. These findings warrant further research into the effect of these drugs on weight gain, skeletal development and growth plate morphology, as well as consideration by physicians treating children and adolescents with ADHD., Competing Interests: Declaration of competing interest None of the authors have any competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite significant differences between men and women in the symptoms of PTSD and the response to therapeutic interventions, most PTSD studies have been done on male subjects. Continuing our previous study in male rats, this study aimed at better understanding the effect of a combination therapy of exercise with fluoxetine on female PTSD rats. The results were then compared with our past findings in male animals. Female adult Wistar rats subjected to PTSD were treated with moderate treadmill exercise or fluoxetine, or a combination of both. PTSD was induced by the single prolonged stress (SPS) model. Elevated plus-maze (EPM), serum and prefrontal BDNF, and fear extinctions were evaluated. The results showed that exercise plus fluoxetine decreased anxiety-like behavior, improved fear extinction, and increased BDNF changes in female rats. The effects of exercise alone were comparable with those of combination therapy except that combination therapy was more effective on OAT (open arm entry). The majority of results in female rats, except for those of prefrontal BDNF, 4th extinction, and OAT, were similar to those of male rats as shown in our previous study. According to our findings, exercise as a safe and cost-effective intervention can be considered as a complementary efficient option for PTSD treatment in both sexes. To achieve better treatment outcomes in PTSD patient, considering sex differences is recommended., (© 2023. The Author(s).)

Since most infectious diseases can develop into sepsis, it is still a major medical problem. Some in-vivo studies showed promising properties of fluoxetine in the treatment of infections. This study aims the antimicrobial effect of fluoxetine on the inflammatory process used in the treatment of sepsis-modeled rats. Besides, to investigate the efficacy of fluoxetine on modifying the antibiotic effect of imipenem in the inflammatory response. An experimental sepsis model was divided into negative control, positive control, fluoxetine 5 mg/kg, imipenem 60 mg/kg, and combined (fluoxetine; imipenem). Procalcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP), lactate, myeloperoxidase activity (MPO), the inflammation markers interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alfa (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) levels were measured by enzyme-linked immunosorbent assay method. Oxidative stress markers, total oxidant status (TOS), total antioxidant status (TAS), total thiol (TT), and native thiol (NT) were measured using photometric methods. Oxidative stress index (OSI) was calculated according to TAS and TOS levels. The statistical analysis was performed by Statistical Package for Social Sciences version 22.0. After treatment with fluoxetine, imipenem, and combined groups, IL-1β, IL-6, TNF-α, MPO activity, MCP-1, hs-CRP, PCT, lactate, and the oxidative stress markers OSI, and disulfide levels were decreased (p < 0.05). The TT, NT, and TAS levels significantly statistically increased (p < 0.05). This research demonstrates that fluoxetine has effects as anti-inflammatory and antioxidant, and the combined treatment with antibioticum imipenem indicates positive synergistic effects in the experimental sepsis model., (© 2022 Wiley Periodicals LLC.)

Since a significant body of studies supports the involvement of glutamatergic neurotransmission in the neurobiology of obsessive-compulsive disorder (OCD). Ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist with rapid and sustained antidepressant effect, raises as a potential new anti-OCD drug. Evidence from pre-clinical studies indicates that female mice are more sensitive than male mice to ketamine antidepressant effects. Our group previously showed that S-ketamine, one ketamine enantiomer, induces an acute anti-compulsive effect in male mice. Herein, we investigated this S-ketamine effect in female adult Swiss mice as monotherapy or as an adjuvant to fluoxetine, a selective serotonin reuptake inhibitor (SSRI), compared to male mice. For this purpose, we assessed the S-ketamine anti-compulsive-like effect in the marble-burying (MBT) and nest-building (NBT) tests in adult female Swiss mice. S-ketamine reduced the compulsive-like behaviour of female mice in both animal tests in a dose larger (30 mg/kg) than the effective dose in male Swiss mice (10 mg/kg, Tosta et al., 2019). The association of sub-effective doses of S-ketamine and fluoxetine effectively reduced the marble-burying behaviour of both male and female Swiss mice, although male mice present a better response. The variation of female sex hormones (oestrogen and progesterone), inferred by oestrous cycle and ovariectomy, did not influence S-ketamine's response. In conclusion, we found that female mice are less sensitive to S-ketamine's anti-compulsive-like effect than male mice as monotherapy or adjuvant treatment, but oscillations in female sex hormones concentrations do not seem to explain this difference., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Chronic social isolation (CSIS)-induced alternation in synaptic and mitochondrial function of specific brain regions is associated with major depressive disorder (MDD). Despite the wide number of available medications, treating MDD remains an important challenge. Although fluoxetine (Flx) is the most frequently prescribed antidepressant, its mode of action is still unknown. To delineate affected molecular pathways of depressive-like behavior and identify potential targets upon Flx treatment, we performed a comparative proteomic analysis of hippocampal purified synaptic terminals (synaptosomes) of rats exposed to six weeks of CSIS, an animal model of depression, and/or followed by Flx treatment (lasting three weeks of six-week CSIS) to explore synaptic protein profile changes. Results showed that Flx in controls mainly induced decreased expression of proteins involved in energy metabolism and the redox system. CSIS led to increased expression of proteins that mainly participate in Ca 2+ /calmodulin-dependent protein kinase II (Camk2)-related neurotransmission, vesicle transport, and ubiquitination. Flx treatment of CSIS rats predominantly increased expression of proteins involved in synaptic vesicle trafficking (exocytosis and endocytosis), and energy metabolism (glycolytic and mitochondrial respiration). Overall, these Flx-regulated changes in synaptic and mitochondrial proteins of CSIS rats might be critical targets for new therapeutic development for the treatment of MDD.