Effect of depression and the antidepressant fluoxetine on osseointegration-A pre-clinical in vivo experimental study.

OBJECTIVE: The aim of this study was to explore the effect of depression and selective serotonin reuptake inhibitors on implant osseointegration and bone healing. METHODS: Forty-eight 6- to 8-week-old SPF Sprague-Dawley male rats were randomly divided into four groups: the Control group, the Fluoxetine group, the Depression group and the De&Flu group. The rats in the Depression group and the De&Flu group were subjected to a depression modelling process, and the rats in the Control group and the Fluoxetine group were raised normally. Then, a titanium implant was placed in the right tibia of each rat. In the Fluoxetine group and De&Flu group, fluoxetine was injected subcutaneously daily, while subcutaneously injecting physiological saline in the Control group and Depression group. Collecting serum from the rats used for ELISA. The surgical area was cut for microcomputed tomography and histology observation. RESULTS: After 12 weeks, bone mineral density was lower in the De&Flu group than in the Control group, Depression group and Fluoxetine group. Bone mineral density was also lower in the Depression group and the Fluoxetine group than in the Control group. The percentage of bone-implant contact (BIC%) in De&Flu rats was lower than in the Control, Depression and Fluoxetine groups. The BIC% in the Depression group and the Fluoxetine group was lower than in the Control group. CONCLUSIONS: Depression and fluoxetine negatively affect bone density and implant osseointegration independently, and this damaging effect is exacerbated when both factors are present. The mechanism may be related to the dysregulation of the hypothalamic-pituitary-adrenal axis and inflammation in the body.

Evaluating non-monotonic dose-response relationships in ecotoxicological risk assessment: a case study based on a systematic review of data on fluoxetine.

The environmental presence of pharmaceuticals, including the antidepressant fluoxetine, has become a subject of concern. Numerous studies have revealed effects of fluoxetine at environmental concentrations. Some of these studies have reported non-monotonic dose-response curves (NMDRs), leading to discussion because of the inconsistent detection of subtle effects and lack of mechanistic understanding. Nevertheless, investigating NMDRs in risk assessment is important, because neglecting them could underestimate potential risks of chemicals at low levels of exposure. Identification and quantification of NMDRs in risk assessment remains challenging, particularly given the prevalence of single outliers and the lack of sound statistical analyses. In response, the European Food Safety Authority (Beausoleil et al. 2016) presented a framework delineating six checkpoints for the evaluation of NMDR datasets, offering a systematic method for their assessment. The present study applies this framework to the case study of fluoxetine, aiming to assess the weight-of-evidence for the reported NMDR relationships. Through a systematic literature search, 53 datasets were selected for analysis against the six checkpoints. The results reveal that while a minority of these datasets meet all checkpoints, a significant proportion (27%) fulfilled at least five. Notably, many studies did not meet checkpoint 3, which requires NMDRs to be based on more than a single outlier. Overall, the current study points out a number of studies with considerable evidence supporting the presence of NMDRs for fluoxetine, while the majority of studies lacks strong evidence. The suggested framework proved useful for analysing NMDRs in ecotoxicological studies, but it is still imperative to develop further understanding of their biological plausibility.

Clinical effect of acupuncture at ghost points combined with fluoxetine hydrochloride on mild-to-moderate depression.

BACKGROUND: Depression is a common, chronic, and recurrent mood disorder that has become a worldwide health hazard. Fluoxetine hydrochloride, a common treatment method, can inhibit 5-hydroxytryptamine (5-HT) recycling in the presynaptic membrane; however, the efficacy of a single drug is inadequate. At present, mild-to-moderate depression can be treated with acupuncture of ghost caves, but the clinical curative effect of combined therapy with fluoxetine hydrochloride has not been sufficiently reported. AIM: To evaluate the clinical effect of acupuncture at ghost points combined with fluoxetine hydrochloride in the treatment of mild-to-moderate depression. METHODS: This retrospective study included 160 patients with mild-to-moderate depression who were admitted to Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, between January 2022 and June 2023. Patients were separated into a single-agent group (fluoxetine hydrochloride treatment, n = 80) and a coalition group (fluoxetine hydrochloride treatment combined with acupuncture at ghost points, n = 80). Pre-treatment symptoms were recorded, and the clinical curative effect and adverse reactions [Asberg Antidepressant Side Effects Scale (SERS)] were assessed. Depression before and after treatment [Hamilton Depression Scale (HAMD)-24], neurotransmitter levels [5-HT, norepinephrine (NE), dopamine (DA)], oxidative stress indicators [superoxide dismutase (SOD), malondialdehyde (MDA)], and sleep quality [Pittsburgh Sleep Quality Index (PSQI)] were compared. RESULTS: The total efficacy rate was 97.50% in the coalition group and 86.25% in the single-agent group (P < 0.05). After 2, 4, 6, and 8 wk of treatment, the HAMD, self-rating depression scale, and SERS scores of the coalition and single-agent groups decreased compared with pre-treatment, and the decrease was more significant in the coalition group (P < 0.05). After 8 wk of treatment, the levels of NE, DA, 5-HT, and SOD in the coalition and single-agent groups increased, while the levels of MDA decreased; the increases and decrease in the coalition group were more significant (P < 0.05). The PSQI scores of the coalition and single-agent groups decreased, and the decrease was more significant in the coalition group (P < 0.05). CONCLUSION: Acupuncture at ghost points combined with paroxetine tablets can safely improve depressive symptoms and sleep disorders, regulate neurotransmitter levels, and reduce stress responses in patients with mild-to-moderate depression.

Fluoxetine and ketamine trigger the p75NTR proteolytic pathway and enhance extinction memory and brain plasticity through p75NTR.

BACKGROUND: Diverse antidepressants were recently described to bind to TrkB and drive a positive allosteric modulation of endogenous BDNF. Although neurotrophins such as BDNF can bind to the p75 neurotrophin receptor (p75NTR), their precursors are the high affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a cross-like conformation dimer and carry a cholesterol-recognition and alignment consensus in the transmembrane domain. Since such qualities were found crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR. METHODS: ELISA-based binding assay and NMR spectroscopy were accomplished to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to address whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase-dependent p75NTR proteolysis, and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75KO mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verifying how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male WT mice and rats. RESULTS: Antidepressants were found binding to p75NTR, FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes. CONCLUSION: We thus hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain ability for remodeling.

Effect analysis of repeated transcranial magnetic stimulation combined with fluoxetine in the treatment of first-episode adolescent depression.

Objectives: This study aims to evaluate the efficacy of repeated transcranial magnetic stimulation (rTMS) combined with fluoxetine in enhancing the early antidepressant response in first-episode adolescent depression cases, providing insights for patient diagnosis and treatment. Methods: One hundred and thirty-five adolescents experiencing their first depressive episode were randomly assigned to either a sham group treated with fluoxetine or to low or high repetitive transcranial magnetic stimulation (rTMS) groups receiving both rTMS and fluoxetine. Therapeutic effects were assessed by comparing changes in Hamilton Depression Scale (HAMD-17) scores, cognitive function scores from the Wisconsin Card Sorting Test (WCST), and Clinical Global Impression-improvement (CGI-I) scores, along with recording adverse reactions. Results: The total effectiveness rate in the rTMS groups (Low, 95.56%; High, 97.78%) was significantly higher than in the Sham rTMS group (80%) (F = 11.15, P<0.0001). Post-treatment, not only the Low but also the High rTMS group exhibited more significant reductions in HAMD-17 (Low, 21.05; High, 21.45) and CGI-I scores (Low, 3.44; High, 3.60) compared to the Sham rTMS group (HAMD-17, 16.05; CGI-I, 2.57) (two weeks: F = 7.889, P = 0.0006; four weeks: F = 15.900, P<0.0001). Additionally, the two rTMS groups exhibited fewer erroneous responses and persistent errors in the WCST and completed more WCST categorizations than the Sham rTMS group. There was no significant difference in adverse reaction rates between the groups (F=4.421, P=0.0794). Conclusions: The combination of fluoxetine with rTMS demonstrates enhanced therapeutic effectiveness in treating adolescent depression, effectively controlling disease progression, reducing depressive symptoms, and improving cognitive function, making it a valuable clinical approach.

Nicotine and fluoxetine alter adolescent dopamine-mediated behaviors via 5-HT1A receptor activation.

Introduction: Abuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when the distinct neurobiology of adolescent serotonin (5-HT) and dopamine (DA) systems create unique behavioral vulnerabilities to drugs of abuse. Methods: Using a pharmacological approach, we modeled the behavioral and neurochemical effects of subchronic (4-day) nicotine (60µg/kg, i.v.) or fluoxetine (1mg/kg, i.v.) exposure in adolescent and adult male rats. Results: Nicotine and fluoxetine significantly enhance quinpirole-induced locomotor activity and initial cocaine self-administration in adolescents, but not adults. These effects were blocked by serotonin 5-HT1A receptor antagonists, WAY-100,635 (100 µg/kg, i.v.) or S-15535 (300 µg/kg, i.v.). Neurochemical and anatomical autoradiographic analysis of 8-OH-DPAT-stimulated [35S]GTPγS reveal that prior exposure to nicotine and fluoxetine results in both overlapping and distinct effects on regional 5-HT1A receptor activity. Both fluoxetine and nicotine enhance adolescent 5-HT1A receptor activity in the primary motor cortex (M1), whereas fluoxetine alone targets prefrontal cortical neurocircuitry and nicotine alone targets the amygdala. Discussion: Given their different pharmacological profiles, comparison between WAY-100,635 and S-15535 indicates that postsynaptic 5-HT1A receptors mediate the behavioral effects of prior nicotine and fluoxetine exposure. In addition, within the adolescent M1, maladaptive changes in 5-HT signaling and 5-HT1A activity after nicotine or fluoxetine exposure may potentiate hyper-responsiveness to dopaminergic drugs and prime adolescent vulnerability for future substance abuse.

Emerging Therapeutic Potential of Fluoxetine on Cognitive Decline in Alzheimer's Disease: Systematic Review.

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 Aß 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.

Effect of an antidepressant on aquatic ecosystems in the presence of microplastics: A mesocosm study.

Emerging pollutants, such as pharmaceuticals and microplastics have become a pressing concern due to their widespread presence and potential impacts on ecological systems. To assess the ecosystem-level effects of these pollutants within a multi-stressor context, we simulated real-world conditions by exposing a near-natural multi-trophic aquatic food web to a gradient of environmentally relevant concentrations of fluoxetine and microplastics in large mesocosms over a period of more than three months. We measured the biomass and abundance of different trophic groups, as well as ecological functions such as nutrient availability and decomposition rate. To explore the mechanisms underlying potential community and ecosystem-level effects, we also performed behavioral assays focusing on locomotion parameters as a response variable in three species: Daphnia magna (zooplankton prey), Chaoborus flavicans larvae (invertebrate pelagic predator of zooplankton) and Asellus aquaticus (benthic macroinvertebrate), using water from the mesocosms. Our mesocosm results demonstrate that presence of microplastics governs the response in phytoplankton biomass, with a weak non-monotonic dose-response relationship due to the interaction between microplastics and fluoxetine. However, exposure to fluoxetine evoked a strong non-monotonic dose-response in zooplankton abundance and microbial decomposition rate of plant material. In the behavioral assays, the locomotion of zooplankton prey D. magna showed a similar non-monotonic response primarily induced by fluoxetine. Its predator C. flavicans, however, showed a significant non-monotonic response governed by both microplastics and fluoxetine. The behavior of the decomposer A. aquaticus significantly decreased at higher fluoxetine concentrations, potentially leading to reduced decomposition rates near the sediment. Our study demonstrates that effects observed upon short-term exposure result in more pronounced ecosystem-level effects following chronic exposure.

Beyond Psychotropic: Potential Repurposing of Fluoxetine toward Cancer Therapy.

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.

Inhibitory modulation of action potentials in crayfish motor axons by fluoxetine.

The goal of this report is to explore how K2P channels modulate axonal excitability by using the crayfish ventral superficial flexor preparation. This preparation allows for simultaneous recording of motor nerve extracellular action potentials (eAP) and intracellular excitatory junctional potential (EJP) from a muscle fiber. Previous pharmacological studies have demonstrated the presence of K2P-like channels in crayfish. Fluoxetine (50 µM) was used to block K2P channels in this study. The blocker caused a gradual decline, and eventually complete block, of motor axon action potentials. At an intermediate stage of the block, when the peak-to-peak amplitude of eAP decreased to ∼60%-80% of the control value, the amplitude of the initial positive component of eAP declined at a faster rate than that of the negative peak representing sodium influx. Furthermore, the second positive peak following this sodium influx, which corresponds to the after-hyperpolarizing phase of intracellularly recorded action potentials (iAP), became larger during the intermediate stage of eAP block. Finally, EJP recorded simultaneously with eAP showed no change in amplitude, but did show a significant increase in synaptic delay. These changes in eAP shape and EJP delay are interpreted as the consequence of depolarized resting membrane potential after K2P channel block. In addition to providing insights to possible functions of K2P channels in unmyelinated axons, results presented here also serve as an example of how changes in eAP shape contain information that can be used to infer alterations in intracellular events. This type of eAP-iAP cross-inference is valuable for gaining mechanistic insights here and may also be applicable to other model systems.

Ketamine and fluoxetine exert similar actions on prelimbic and infralimbic responsivity to lateral septal nucleus stimulation in Wistar rats.

Ketamine is a dissociative anesthetic that has been proposed to be a useful alternative in cases of a poor response to other treatments in patients with depression. Remarkably, beneficial clinical actions of ketamine are detected once its psychotropic actions disappear. Therefore, clinical actions may occur independently of dose. Most current studies focus on actions of ketamine on neurotrophic factors, but few studies have investigated actions of ketamine on neural structures for which actions of antidepressants have been previously explored. Lateral septal nucleus (LSN) stimulation reduces neural activity in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Fluoxetine increases inhibitory responsivity of the LSN-IL connection. In the present study, actions of an anesthetic dose of ketamine were compared with a high dose of fluoxetine on behavior and neural responsivity 24 h after drug administration. Fluoxetine reduced immobility in the forced swim test without changing locomotor activity in the open field test. Ketamine strongly decreased locomotor activity and did not produce changes in immobility. In another set of Wistar rats that received similar drug treatment regimens, the results indicated that LSN stimulation in saline-treated animals produced a long-lasting inhibitory afterdischarge in these mPFC subregions. Actions of ketamine on the LSN-mPFC connection reproduced actions of fluoxetine, consisting of accentuated inhibition of the LSN action on the mPFC. These findings suggest that independent of different actions on neurotransmission, the common final pathway of antidepressants lies in their actions on forebrain structures that are related to emotional regulation.

ß-arrestin2 is indispensable for the antidepressant effects of fluoxetine via inhibiting astrocytic pyroptosis in chronic mild stress mouse model for depression.

ß-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of ß-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and ß-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 ß-arrestin2-/- CMS group, these results of the ß-arrestin2-/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out ß-arrestin2. Mass spectrometry implying that FLX promoted the binding of ß-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to ß-arrestin2. We further found that the lack of ß-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, ß-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT2BR-ß-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.

The impacts of natural product miltirone and the CYP2D6 pharmacogenetic phenotype on fluoxetine metabolism.

Introduction: To study the effects of drug-induced CYP2D6 activity inhibition and genetic polymorphisms on fluoxetine metabolism, rat liver microsomes (RLMs) and SD rats were used to investigate the potential drug‒drug interactions (DDIs), and CYP2D6 http://muchong.com/t-10728934-1 recombinant baculosomes were prepared and subjected to catalytic reactivity studies. Methods and Results: All analytes were detected by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC‒MS/MS). After screening for 27 targeted natural products, miltirone was identified as having obvious inhibitory effect on fluoxetine metabolism in RLMs. In vivo, the concentration of fluoxetine in rat blood increased markedly after miltirone administration. The molecular docking results showed that miltirone bound more strongly to CYP2D6 than fluoxetine, and PHE120 may be the key residue leading to the inhibition of CYP2D6-mediated fluoxetine N-demethylation by miltirone. In terms of the genetic polymorphism of CYP2D6 on fluoxetine metabolism, the intrinsic clearance values of most variants were significantly altered. Among these variants, CYP2D6*92 and CYP2D6*96/Q424X were found to be catalytically inactive for fluoxetine metabolism, five variants (CYP2D6*89/L142S, *97/F457L, *R497, *V342M and *R344Q) exhibited markedly increased clearance values (>125.07%) and seven variants (CYP2D6*2, *10, *87/A5V, *93/T249P, *E215K, *R25Q and *R440C) exhibited significantly decreased clearance values (from 6.62% to 66.79%) compared to those of the wild-type. Conclusion: Our results suggest that more attention should be given to subjects in the clinic who take fluoxetine and also carry one of these infrequent CYP2D6 alleles or are coadministered drugs containing miltirone.

Effects of esketamine and fluoxetine on depression-like behaviors in chronic variable stress: a role of plasma inflammatory factors.

Mounting evidence has identified the rapid and sustained antidepressive and anxiolytic-like effects of esketamine. However, the underlying mechanism of this no-monoamine target rapid-onset antidepressant is still underexplored. Immune-inflammatory pathways and cell-mediated immune activation, mainly including inflammatory cytokines in plasma, play a pivotal role in the pathogenesis of major depressive disorder and are also a potential therapeutic target for MDD. The current study was designed to clarify the role of esketamine on the expression of plasma cytokines in a depressive-like model introduced by chronic variable stress (CVS). In this study, a 21-day consecutive CVS protocol was applied to produce depressive- and anxiety-like behaviors. After the single dose or 7-day repeated administration of esketamine or fluoxetine, the depressive- and anxiety-like behaviors and the expression of inflammatory cytokines in plasma were examined. Both a single dose of esketamine and 7-days repeated fluoxetine administration elicited anti-depressive and anxiolytic effects in mice exposed to CVS. Additionally, CVS produced significant changes in the plasma inflammatory factors, notably increasing the expression of IL-1ß, IL-6, IL-8, IL-17A, TNFα, IL-4, IL-9, IL-24, IL-37, IFN-ß, and CXCL12, while reducing IL-10 and IL-33. With the administration of esketamine and fluoxetine, CVS-produced inflammatory disturbances were partially normalized. Together, our findings provide a novel insight that acute esketamine treatment could rescue CVS-produced depressive-like and anxiety-like behaviors in mice by normalizing the expression of inflammatory cytokines; this effect was similar to the repeated administration of fluoxetine. These results contributed to the understating of rapid anti-depressant effects elicited by esketamine.

The impact of chronic fluoxetine treatment in adolescence or adulthood on context fear memory and perineuronal nets.

Selective serotonin reuptake inhibitors, such as fluoxetine (Prozac), are commonly prescribed pharmacotherapies for anxiety. Fluoxetine may be a useful adjunct because it can reduce the expression of learned fear in adult rodents. This effect is associated with altered expression of perineuronal nets (PNNs) in the amygdala and hippocampus, two brain regions that regulate fear. However, it is unknown whether fluoxetine has similar effects in adolescents. Here, we investigated the effect of fluoxetine exposure during adolescence or adulthood on context fear memory and PNNs in the basolateral amygdala (BLA), the CA1 subregion of the hippocampus, and the medial prefrontal cortex in rats. Fluoxetine impaired context fear memory in adults but not in adolescents. Further, fluoxetine increased the number of parvalbumin (PV)-expressing neurons surrounded by a PNN in the BLA and CA1, but not in the medial prefrontal cortex, at both ages. Contrary to previous reports, fluoxetine did not shift the percentage of PNNs toward non-PV cells in either the BLA or CA1 in the adults, or adolescents. These findings demonstrate that fluoxetine differentially affects fear memory in adolescent and adult rats but does not appear to have age-specific effects on PNNs.

Structure-Activity Relationship Analysis of Fluoxetine for Suppression of Inflammatory Cytokine Production.

There is accumulating evidence that selective serotonin reuptake inhibitors (SSRIs), clinically used as antidepressants, have a beneficial effect on inflammatory diseases such as coronavirus disease 2019 (COVID-19). We previously compared the inhibitory effects of five U.S. Food and Drug Administration (FDA)-approved SSRIs on the production of an inflammatory cytokine, interleukin-6 (IL-6), and concluded that fluoxetine (FLX) showed the most potent anti-inflammatory activity. Here, we investigated the structure-activity relationship of FLX for anti-inflammatory activity towards J774.1 murine macrophages. FLX suppressed IL-6 production induced by the TLR3 agonist polyinosinic-polycytidylic acid (poly(I : C)) with an IC50 of 4.76 µM. A derivative of FLX containing chlorine instead of the methylamino group lacked activity, suggesting that the methylamino group is important for the anti-inflammatory activity. FLX derivatives bearing an N-propyl or N-(pyridin-3-yl)methyl group in place of the N-methyl group exhibited almost the same activity as FLX. Other derivatives showed weaker activity, and the N-phenyl and N-(4-trifluoromethyl)benzyl derivatives were inactive. The chlorine-containing derivative also lacked inhibitory activity against TLR9- or TLR4-mediated IL-6 production. These derivatives showed similar structure-activity relationships for TLR3- and TLR9-mediated inflammatory responses. However, the activities of all amino group-containing derivatives against the TLR4-mediated inflammatory response were equal to or higher than the activity of FLX. These results indicate that the substituent at the nitrogen atom in FLX strongly influences the anti-inflammatory effect.

Fluoxetine Successfully Treats Intracranial Enterovirus E18 Infection in a Patient with CD79a Deficiency Arising from Segmental Uniparental Disomy of Chromosome 19.

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 Igß 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.

Fluoxetine attenuates chlorpyrifos-induced neuronal injury through the PPARγ, SIRT1, NF-κB, and JAK1/STAT3 signals.

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 Aß 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-1ß, 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.

Effects of two commonly used antidepressants amitriptyline and fluoxetine on the pharmacokinetics of abrocitinib in rats.

Abrocitinib is approved to treat moderate-to-severe atopic dermatitis and eliminated mainly through cytochrome P450 (CYP450) enzyme. Two commonly used antidepressants, amitriptyline and fluoxetine, could inhibit the activities of CYP2C19 and CYP3A4. In this study, we developed a new and quick ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantitatively analyzing the plasma concentration of abrocitinib, and further investigated the effects of amitriptyline or fluoxetine on the pharmacokinetics of abrocitinib in rats. The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied according to the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Our result showed that when co-administered with amitriptyline and fluoxetine, the CLz/F of abrocitinib was reduced by 44.4 % and 33.3 %, respectively, while the AUC(0-t) of abrocitinib was increased by 77.7 % and 49.4 %, respectively. It indicated that amitriptyline and fluoxetine could significantly increase the plasma concentration of abrocitinib in rats. Thus, dose adjustment of abrocitinib may be required when it is combined with amitriptyline or fluoxetine in ongoing clinical practice.

Presumed fluoxetine maculopathy.

To report a unique case of a patient who developed simultaneous bilateral maculopathy presumed from intake of fluoxetine. The optic coherence tomography (OCT) macular showed a subfoveal disruption in the outer retinal layer in both eyes (OU), higher in the left one (OS). Although reported cases of serotonin recapture inhibitors (SSRIs) Maculopathy so far have been caused by sertraline, fluoxetine shares the biological mechanism, and OCT findings and ocular symptoms are the same as published. We should be aware with ocular symptoms in patients that take fluoxetine.